Showing papers in "Journal of Medicinal Chemistry in 2010"
TL;DR: A number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens are described.
Abstract: This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are not recognized by filters commonly used to identify reactive compounds. Even though these substructural features were identified using only one assay detection technology, such compounds have been reported to be active from many different assays. In fact, these compounds are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
2,791 citations
TL;DR: This article compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems.
Abstract: Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their three-dimensional structures. This optimization process requires knowledge about interaction geometries and approximate affinity contributions of attractive interactions that can be gleaned from crystal structure and associated affinity data.
Here we compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems. We attempt to extract key messages of practical value and complement references with our own searches of the CSDa,(1) and PDB databases.(2) The focus is on direct contacts between ligand and protein functional groups, and we restrict ourselves to those interactions that are most frequent in medicinal chemistry applications. Examples from supramolecular chemistry and quantum mechanical or molecular mechanics calculations are cited where they illustrate a specific point. The application of automated design processes is not covered nor is design of physicochemical properties of molecules such as permeability or solubility.
Throughout this article, we wish to raise the readers’ awareness that formulating rules for molecular interactions is only possible within certain boundaries. The combination of 3D structure analysis with binding free energies does not yield a complete understanding of the energetic contributions of individual interactions. The reasons for this are widely known but not always fully appreciated. While it would be desirable to associate observed interactions with energy terms, we have to accept that molecular interactions behave in a highly nonadditive fashion.3,4 The same interaction may be worth different amounts of free energy in different contexts, and it is very hard to find an objective frame of reference for an interaction, since any change of a molecular structure will have multiple effects. One can easily fall victim to confirmation bias, focusing on what one has observed before and building causal relationships on too few observations. In reality, the multiplicity of interactions present in a single protein−ligand complex is a compromise of attractive and repulsive interactions that is almost impossible to deconvolute. By focusing on observed interactions, one neglects a large part of the thermodynamic cycle represented by a binding free energy: solvation processes, long-range interactions, conformational changes. Also, crystal structure coordinates give misleadingly static views of interactions. In reality a macromolecular complex is not characterized by a single structure but by an ensemble of structures. Changes in the degrees of freedom of both partners during the binding event have a large impact on binding free energy.
The text is organized in the following way. The first section treats general aspects of molecular design: enthalpic and entropic components of binding free energy, flexibility, solvation, and the treatment of individual water molecules, as well as repulsive interactions. The second half of the article is devoted to specific types of interactions, beginning with hydrogen bonds, moving on to weaker polar interactions, and ending with lipophilic interactions between aliphatic and aromatic systems. We show many examples of structure−activity relationships; these are meant as helpful illustrations but individually can never confirm a rule.
1,162 citations
TL;DR: This research presents a novel, scalable, and scalable approaches that can be applied to the rapidly changing and rapidly changing environment of drug discovery and development.
Abstract: Fraser F. Fleming,* Lihua Yao, P. C. Ravikumar, Lee Funk, and Brian C. Shook Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, Mylan Pharmaceuticals Inc., 781 Chestnut Ridge Road, Morgantown, West Virginia 26505, and Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477
1,058 citations
TL;DR: Phosphoramidate prodrugs of the 5'-phosphate derivative of the β-d- 2'-deoxy-2'-α-fluoro-2-β-C-methyluridine nucleoside showed significant potency in the HCV subgenomic replicon assay and produced high levels of triphosphates 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo.
Abstract: Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5′-phosphate derivative of the β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977...
617 citations
TL;DR: This research presents a novel and scalable approaches that allow for real-time decision-making in the design and implementation of drug 505(b) agonist regimens for the treatment of central nervous system disorders.
Abstract: Tony Velkov,* Philip E. Thompson, Roger L. Nation, and Jian Li* School of Medicine, Deakin University, Pigdons Road, Geelong 3217, Victoria, Australia, Medicinal Chemistry and Drug Action and Facility for Anti-infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia
597 citations
TL;DR: It is found that changes in these properties depend on a subtle balance between the strength of the hydrogen bond interaction, geometry of the newly formed ring system, and the relative energies of the open and closed conformations in polar and unpolar environments.
Abstract: The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we derive propensities for intramolecular hydrogen bond formation of five- to eight-membered ring systems of relevance in drug discovery. A number of motifs, several of which are clearly underutilized in drug discovery, are analyzed in more detail by comparing small molecule and protein-ligand X-ray structures. To investigate effects on physicochemical properties, sets of closely related structures with and without the ability to form intramolecular hydrogen bonds were designed, synthesized, and characterized with respect to membrane permeability, water solubility, and lipophilicity. We find that changes in these properties depend on a subtle balance between the strength of the hydrogen bond interaction, geometry of the newly formed ring system, and the relative energies of the open and closed conformations in polar and unpolar environments. A number of general guidelines for medicinal chemists emerge from this study.
453 citations
TL;DR: The use of folic acid as a ligand to target therapeutic cargos of many sizes, shapes, and mechanisms of action to tumor cells both in vitro and in vivo is reviewed.
Abstract: 1.1. General Strategies in the Design of Tumor Targeted Therapeutics. Today’s quest for developing tumor-targeted therapies has naturally followed two nonoverlapping strategies. The first strategy involves pursuing agents that can selectively block novel pathways or proteins that emerge or become overexpressed in malignant cells. These pathways are generally critical for tumor cell survival but are either not present or not needed to a similar extent by normal cells. Examples of this type of targeted therapy include Gleevec (imatinib), a kinase inhibitor that targets the fusion protein bcr/abl, which arises solely from a chromosomal translocation during tumorigenesis, and Avastin (bevacizumab), a monoclonal antibody that suppresses neoangiogenesis required to nourish tumors for proliferation. The pharmaceutical industry is currently focusing its efforts almost exclusively on this type of targeted therapeutic agent. The second strategy involves the use of a homing ligand that binds specifically to a receptor that is expressed primarily on malignant cells. When linked to a therapeutic drug, this ligand can be exploited to carry the nonselective drug specifically into the cancer cell. If the drug is released only after internalization by the diseased cell, unwanted collateral damage to receptornegative tissues can be avoided. Thus, wherever appropriately specific ligands can be identified, they can be exploited to convert nonspecific cytotoxic drugs into finely tuned tumorspecific warheads. Ligands that have been exploited for this approach to tumor targeting includemonoclonal antibodies and low molecular weight receptor-binding molecules such as peptide hormones, receptor antagonists and agonists, oligosaccharides, oligopeptides, and vitamins. This article will review the use of folic acid as a ligand to target therapeutic cargos of many sizes, shapes, and mechanisms of action to tumor cells both in vitro and in vivo. For reviews of the use of folic acid to deliver attached imaging agents to malignant masses, the reader is referred to other published articles. 1.2. Pros and Cons of Ligand-Targeted Therapies. Ligandtargeted therapies offer several advantages over the aforementioned functionality-targeted therapies, themost notable being the former’s remarkable flexibility and adaptability. Almost any potent drug can be targeted to a tumor tissue if it can be linked reversibly to a targeting ligand with specificity for a pathologic cell type. A second advantage is that a cognate imaging agent can almost always be synthesizedusing the same targeting ligand, and this targeted imaging agent can then be employed to select for patients whose tumors overexpress the ligand’s receptor. Third, ligand-targeted therapies are generally preferred for delivery of membrane-impermeable drugs because a good targeting ligand can convey its attached cargo into the target cell by receptor-mediated endocytosis, rendering an otherwise membrane impermeable drug more efficacious. And finally, because overexpression of a receptor on cancer cells is usually a more common event than over-reliance on an enzyme unique to cancer cells (e.g., bcr/ abl),more development potentialmay exist for ligand-targeted therapies than functionality-targeted therapies. Development of ligand-targeted therapies also poses several challenges that are absent from functionality-targeted and nontargeted therapies. First, because most endocytic pathways transport relatively fewmolecules into a cell, the ligand-targeted drug must be effective at low concentrations. This can be problematic for diseases for which few highly potent drugs have been identified. Second, delivery to the correct site does not necessarily guarantee therapeutic efficacy; rather, the drug generally not only must be internalized by the cell but also must be released within the cell. Because only a few chemical functionalities allow for facile release of a covalently attached drug after targeted cell uptake, drugs must contain at least one of a limited numberof chemicalmoieties (-SH,-COOH,-OH,or-NH2) that can be adapted for intracellular release. Third, an efficient drug release mechanism must be designed into the conjugate: one that is inert during transit to the pathologic lesion but is activated rapidly after target cell binding and internalization, enabling release of the therapeutic cargo only at the site of disease. Not all ligand-targeted conjugates lend themselves to such mechanisms. And finally, for some membrane-impermeabledrugs, anendosomeescape strategymustbedesigned.Thus, after receptor-mediated endocytosis, the drug will generally still need to pass through the endosomal membrane to reach its target within the pathologic cell. While much progress has been made in developing these endosomal escape mechanisms, more improvements are needed before the full potential of ligandtargetedmacromolecular drugs (such as siRNAs, proteins, and nanoparticles) can be realized.
428 citations
421 citations
TL;DR: In the ER and mitochondria, the Hsp70 family members are thought to fulfill specific functions and have unique substrates, with BiP playing key roles in the folding and quality control of ER proteins and mtHsp70 being involved in the import and export of proteins from the mitochondria.
Abstract: Heat shock protein 70 (Hsp70) is a molecular chaperone that is expressed in response to stress. In this role, Hsp70 binds to its protein substrates and stabilize them against denaturation or aggregation until conditions improve.1 In addition to its functions during a stress response, Hsp70 has multiple responsibilities during normal growth; it assists in the folding of newly synthesized proteins,2, 3 the subcellular transport of proteins and vesicles,4 the formation and dissociation of complexes,5 and the degradation of unwanted proteins.6, 7 Thus, this chaperone broadly shapes protein homeostasis by controlling protein quality control and turnover during both normal and stress conditions.8 Consistent with these diverse activities, genetic and biochemical studies have implicated it in a range of diseases, including cancer, neurodegeneration, allograft rejection and infection. This review provides a brief review of Hsp70 structure and function and then explores some of the emerging opportunities (and challenges) for drug discovery.
Hsp70 is Highly Conserved
Members of the Hsp70 family are ubiquitously expressed and highly conserved; for example, the major Hsp70 from Escherichia coli, termed DnaK, is approximately 50% identical to human Hsp70s.9 Eukaryotes often express multiple Hsp70 family members with major isoforms found in all the cellular compartments: Hsp72 (HSPA1A) and heat shock cognate 70 (Hsc70/HSPA8) in the cytosol and nucleus, BiP (Grp78/HSPA5) in the endoplasmic reticulum and mtHsp70 (Grp75/mortalin/HSPA9) in mitochondria. Some of the functions of the cytosolic isoforms, Hsc70 and Hsp72, are thought to be redundant, but the transcription of Hsp72 is highly responsive to stress and Hsc70 is constitutively expressed. In the ER and mitochondria, the Hsp70 family members are thought to fulfill specific functions and have unique substrates, with BiP playing key roles in the folding and quality control of ER proteins and mtHsp70 being involved in the import and export of proteins from the mitochondria. For the purposes of this review, we will often use Hsp70 as a generic term to encompass the shared properties of the family members.
395 citations
TL;DR: Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.
Abstract: The antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. Racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type Plasmodium falciparum with an in vitro IC(50) of 90 nM. Structure-activity relationships for the optimization of 1 to compound 20a (IC(50) = 0.2 nM) including the identification of the active 1R,3S enantiomer and elimination of metabolic liabilities is presented. Improvement of the pharmacokinetic profile of the series translated to exceptional oral efficacy in the P. berghei infected malaria mouse model where full cure was achieved in four of five mice with three daily doses of 30 mg/kg.
370 citations
TL;DR: It is apparent that new anti-HIV drugs with acceptable toxicity and resistance profiles and, more importantly, new anti -HIV agents with novel mechanisms of action are clearly needed.
Abstract: The human immunodeficiency virus (HIV) has now been established as the causative agent of the acquired immunodeficiency syndrome (AIDS) for over 20 years. During this time an unprecedented success has been achieved in discovering anti-HIV drugs as reflected by the fact that there are now more drugs approved for the treatment of HIV than for all other viral infections taken together. The currently Food and DrugAdministration (FDA) approved anti-HIVdrugs can be divided into seven groups: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). This arsenal of drugs, which is used in combinations, has moved the prognosis of HIV patients from that of high morbidity and mortality to, for many at least, a chronic, manageable but still complex disease. However, the use of these drugs has been relatively limited by their toxicity, drug resistance development, and more worryingly, the fact that some newly HIV-infected patients carry viruses that are already resistant to the currently approvedAIDS treatments. These issues along with drug-related side effects as well as, in some cases, poor tolerability of these drugs make it apparent that new anti-HIV drugs with acceptable toxicity and resistance profiles and, more importantly, new anti-HIV agents with novel mechanisms of action are clearly needed.
TL;DR: A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
Abstract: We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
TL;DR: A new series of variously substituted coumarins and a thiocoumarin for their interaction with 13 mammalian CA isoforms, detecting low nanomolar and isoform selective inhibitors, afford isoform-selective CAIs with various biomedical applications, which render these classes of compounds superior to the clinically used sulfonamides.
Abstract: Coumarin derivatives were recently shown to constitute a totally new class of inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), being hydrolyzed within the CA active site to 2-hydroxycinnamic acids. We explore here a new series of variously substituted coumarins and a thiocoumarin for their interaction with 13 mammalian CA isoforms, detecting low nanomolar and isoform selective inhibitors. The mechanism of action of this class of inhibitors is delineated in detail by resolving the X-ray crystal structure of CA II in complex with trans-2-hydroxy-cinnamic acid, the in situ hydrolysis product of simple coumarin. Thiocoumarins also act as efficient CAIs, similarly to coumarins. The versatility of the (thio)coumarin chemistry, the cis-trans isomerization evidenced here, and easy derivatization of the (thio)coumarin rings, coupled with the nanomolar inhibition range of several isozymes, afford isoform-selective CAIs with various biomedical applications, which render these classes of compounds superior to the clinically used sulfonamides.
TL;DR: Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations, leading to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Abstract: Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia
TL;DR: Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
Abstract: There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for...
TL;DR: The major PARP-1 medicinal chemistry programs will be highlighted focusing on the lead generation, lead optimization, candidate selection, and clinical progress, most of which predated the disclosure of clinical candidate structures and recent clinical trial results.
Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) has been an actively pursued drug discovery target for almost 3 decades. Often referred to as the “guardian angel of DNA”, this abundant nuclear enzyme has been the focus of over 20 medicinal chemistry programs in a wide range of therapeutic areas encompassing stroke, cardiac ischemia, cancer, inflammation, anddiabetes (Figure 1).Despite the great therapeutic potential for this target and the tremendous academic and industrial efforts dedicated to it, only recently have PARP-1 inhibitors made headway in clinical trials. Recent results from several PARP-1 inhibitors in phase II clinical trials for cancer therapyhave attracted the attentionofnationalmedia.Of the several potential therapeutic indications for PARP-1 inhibitors, the two major areas that hold the most promise are ischemia and cancer. This review is structured to provide the readers with a brief summary of the rationale for PARP-1 as a therapeutic target, to explain the PARP-1 inhibitor pharmacophore, and to provide an update on the progress of the PARP-1 drug discovery programs. This Perspective will offer a historical account of the critical PARP-1 publications that instilled the interest of the biopharmaceutical industry in the late 1980s and early 1990s. Furthermore, I will discuss why PARP-1 received somuch attention in the late 1990s and early 2000s followed by the slight decline in themedicinal chemistry efforts today (Figure 1). The major PARP-1 medicinal chemistry programs will be highlighted focusing on the lead generation, lead optimization, candidate selection, and clinical progress.Many aspects of the biological functions of PARP-1 fall outside the scope of this medicinal chemistry review. For this reason, the reader should refer to the following citations for a review of the PARP family of enzymes, the biological functions of poly(ADP-ribose), PARP-1 and intracellular signaling, PARP and DNA repair, PARP and epigenetics, PARP and angiogenesis, and the role of PARP-1 in inflammation. The 30 years of medicinal chemistry on this topic have also afforded some excellent medicinal chemistry reviews, most of which predated the disclosure of clinical candidate structures and recent clinical trial results.
TL;DR: Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells, and coupled with a favorable ADME profile, support the potential of 20G to be an effective treatment for CML, including patients refractory to all currently approved therapies.
Abstract: In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.
TL;DR: This paper presents a meta-analyses of Cheminformatics Software and its Applications for BioMedical Research, aiming at determining the “building blocks” of peptide-based drug discovery and development.
Abstract: Andrew R. Leach,* ) Valerie J. Gillet, Richard A. Lewis, and Robin Taylor Computational and Structural Chemistry, GlaxoSmithKline Research & Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., Department of Information Studies, University of Sheffield, Regent Court, 211 Portobello Street, Sheffield S1 4DP, U.K., Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland, and Taylor Cheminformatics Software, 54 Sherfield Avenue, Rickmansworth, Herts WD3 1NL, U.K.
TL;DR: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340.
Abstract: David C. Pryde,* Deepak Dalvie, Qiyue Hu, Peter Jones, R. Scott Obach, ) and Thien-Duc Tran WorldWide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, England, Pharmacokinetics, Dynamics andMetabolism, Pfizer Global Research andDevelopment, 10628 ScienceCenterDrive, La Jolla, California 92121, WorldWide Medicinal Chemistry, Pfizer Global Research and Development, 10628 Science Center Drive, La Jolla, California 92121, and ) Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340
TL;DR: A rich chemistry of oxetan-3-one and derived Michael acceptors provide venues for the preparation of a broad variety of novel oxetanes not previously documented, thus providing the foundation for their broad use in chemistry and drug discovery.
Abstract: An oxetane can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups. The magnitude of these changes depends on the structural context. Thus, by substitution of a gem-dimethyl group with an oxetane, aqueous solubility may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degradation in most cases. The incorporation of an oxetane into an aliphatic chain can cause conformational changes favoring synclinal rather than antiplanar arrangements of the chain. Additionally spirocyclic oxetanes (e.g., 2-oxa-6-aza-spiro[3.3]heptane) bear remarkable analogies to commonly used fragments in drug discovery, such as morpholine, and are even able to supplant the latter in its solubilizing ability. A rich chemistry of oxetan-3-one and derived Michael acceptors provide venues for the preparation of a broad variety of novel oxetanes not previously...
TL;DR: Studies of compound 5 on HSC-2 cells showed almost exclusive localization to mitochondria, induction of G(2)/M-phase cell cycle block, and onset of apoptosis, suggesting Iodinated BODIPY structures may have potential as new photodynamic therapy agents for cancer.
Abstract: To understand the effects of substitution patterns on photosensitizing the ability of boron dipyrromethene (BODIPY), two structural variations that either investigate the effectiveness of various iodinated derivatives to maximize the "heavy atom effect" or focus on the effect of extended conjugation at the 4-pyrrolic position to red-shift their activation wavelengths were investigated. Compounds with conjugation at the 4-pyrrolic position were less photocytotoxic than the parent unconjugated compound, while those with an iodinated BODIPY core presented better photocytotoxicity than compounds with iodoaryl groups at the meso-positions. The potency of the derivatives generally correlated well with their singlet oxygen generation level. Further studies of compound 5 on HSC-2 cells showed almost exclusive localization to mitochondria, induction of G(2)/M-phase cell cycle block, and onset of apoptosis. Compound 5 also extensively occluded the vasculature of the chick chorioallantoic membrane. Iodinated BODIPY structures such as compound 5 may have potential as new photodynamic therapy agents for cancer.
TL;DR: Investigation of gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione.
Abstract: Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands 1a−4a represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by 1a−4a in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex (2a) revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochon...
TL;DR: A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.
Abstract: A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.
TL;DR: The aim for themedicinal chemistworking in the MKI field should be to strike the right balance between the nonselectivity that may be required for efficacy and the selectivity that is required for safety, especially for the treatment of cancer.
Abstract: Protein kinases have become the second most exploited group of drug targets after G-protein-coupled receptors (GPCRs), accounting for 30% of drug discovery projects at many pharmaceutical companies with dozens of compounds in clinical development. Most early kinase inhibitors exhibited poor selectivity between kinases, and the trend in recent years has been toward ever more selective inhibitors in an attempt to minimize the risk of side effects. The risk with highly selective inhibitors is that their efficacy for treating complex diseases like cancer might be compromised by the redundancies in signaling pathways. The increasing interest in multitarget drug discovery (MTDD) stems froma belief that modulating more than one target can provide superior efficacy and safety profiles compared to single target drugs. Currently, there are two contrasting MTDD philosophies. The first involves combining agents that are selective for a single target to achieve an additive or synergistic effect. The second involves discovering agents that are simultaneously capable of addressing two or more targets. Although this perspective focuses primarily on the latter, the advantages and disadvantages of both approaches will be highlighted. Very few drugs are truly selective for a single target, and in reality most biologically active small molecules have a degree of promiscuity by their very nature. Many clinically useful drugs are now known to have multiple activities, but most of these multitarget drugs (MTDs) were discovered serendipitously and their mechanisms of action were only established retrospectively. The deliberate and prospective design of ligands that act in a “selectively nonselective” manner on multiple targets of therapeutic interest is an emerging trend in drug discovery. Increasing numbers of these so-called designed multiple ligands (DMLs) are being reported in the medicinal chemistry literature. In particular, identifying multikinase inhibitors (MKIs) with specific multiple activity profiles is currently an area of great interest in the pharmaceutical industry, especially for the treatment of cancer. Five years ago there were few examples of DMLs in the medicinal chemistry literature for kinase targets, but the period since has witnessed an explosive growth in interest in this area. Marketed MKI drugs vary with respect to the number of kinases they are known to inhibit, with some inhibiting only a small number of kinases, whereas others appear to be highly promiscuous. These apparent differences in selectivity are to an extent influenced by the amount of selectivity screening that has been performed,with some inhibitors appearing to be more promiscuous simply on the basis of having been profiled more rigorously. As the title of this Perspective delineates, the aim for themedicinal chemistworking in theMKI field should be to strike the right balance between the nonselectivity (promiscuity) that may be required for efficacy and the selectivity that is required for safety. At present it is difficult to intentionally design aMKIwith activity only at the kinases of interest, but increasingly rational and elegant medicinal chemistry approaches are being applied to solving this difficult problem. This Perspective aims to capture the current state of the art and to explore the future challenges and strategies in this area. The terminology used herein, illustrated using known inhibitors, is summarized in Figure 1.
TL;DR: The eight contributions here provide ample evidence that shape as a volume or as a surface is a vibrant and useful concept when applied to drug discovery, and that as computation has enabled the authors' intuition, molecular shape has consistently surprised us in its usefulness and adaptability.
Abstract: The eight contributions here provide ample evidence that shape as a volume or as a surface is a vibrant and useful concept when applied to drug discovery. It provides a reliable scaffold for "decoration" with chemical intuition (or bias) for virtual screening and lead optimization but also has its unadorned uses, as in library design, ligand fitting, pose prediction, or active site description. Computing power has facilitated this evolution by allowing shape to be handled precisely without the need to reduce down to point descriptors or approximate metrics, and the diversity of resultant applications argues for this being an important step forward. Certainly, it is encouraging that as computation has enabled our intuition, molecular shape has consistently surprised us in its usefulness and adaptability. The first Aurelius question, "What is the essence of a thing?", seems well answered, however, the third, "What do molecules do?", only partly so. Are the topics covered here exhaustive, or is there more to come? To date, there has been little published on the use of the volumetric definition of shape described here as a QSAR variable, for instance, in the prediction or classification of activity, although other shape definitions have been successful applied, for instance, as embodied in the Compass program described above in "Shape from Surfaces". Crystal packing is a phenomenon much desired to be understood. Although powerful models have been applied to the problem, to what degree is this dominated purely by the shape of a molecule? The shape comparison described here is typically of a global nature, and yet some importance must surely be placed on partial shape matching, just as the substructure matching of chemical graphs has proved useful. The approach of using surfaces, as described here, offers some flavor of this, as does the use of metrics that penalize volume mismatch less than the Tanimoto, e.g., Tversky measures. As yet, there is little to go on as to how useful a paradigm this will be because there is less software and fewer concrete results.Finally, the distance between molecular shapes, or between any shapes defined as volumes or surfaces, is a metric property in the mathematical sense of the word. As yet, there has been little, if any, application of this observation. We cannot know what new application to the design and discovery of pharmaceuticals may yet arise from the simple concept of molecular shape, but it is fair to say that the progress so far is impressive.
TL;DR: A set of druggable and nondruggable cavities has been compiled in a collaborative platform that can be used, contributed, and curated by the community and reveals that polar groups in druggability binding sites have properties that enable them to play a decisive role in ligand recognition.
Abstract: Druggability predictions are important to avoid intractable targets and to focus drug discovery efforts on sites offering better prospects. However, few druggability prediction tools have been released and none has been extensively tested. Here, a set of druggable and nondruggable cavities has been compiled in a collaborative platform (http://fpocket.sourceforge.net/dcd) that can be used, contributed, and curated by the community. Druggable binding sites are often oversimplified as closed, hydrophobic cavities, but data set analysis reveals that polar groups in druggable binding sites have properties that enable them to play a decisive role in ligand recognition. Finally, the data set has been used in conjunction with the open source fpocket suite to train and validate a logistic model. State of the art performance was achieved for predicting druggability on known binding sites and on virtual screening experiments where druggable pockets are retrieved from a pool of decoys. The algorithm is free, extremel...
TL;DR: The present work presents a meta-analysis of eightiments conducted in Napoli in the period of May 21 to 29, 1997 on the phytochemical properties of manure and its application as a raw material for animal feed.
Abstract: Giuseppe Caliendo,* Giuseppe Cirino, Vincenzo Santagada, and John L. Wallace Dipartimento di Chimica Farmaceutica e Tossicologica, and Dipartimento di Farmacologia Sperimentale, Universit a degli Studi di Napoli Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy, and Farncombe Family Digestive Health Research Institute, McMaster University, 1200 Main Street West, Room HSC-3N9, Hamilton, Ontario, L8N 3Z5, Canada
TL;DR: Novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease and show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals.
Abstract: Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Abeta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier model.