Journal ArticleDOI
The influence of drug-like concepts on decision-making in medicinal chemistry
TLDR
Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development.Abstract:
The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.read more
Citations
More filters
Journal ArticleDOI
Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus
Na Liu,Lei Wei,Li Huang,Fei Yu,Fei Yu,Weifan Zheng,Bingjie Qin,Dong Qin Zhu,Susan L. Morris-Natschke,Shibo Jiang,Shibo Jiang,Chin Ho Chen,Kuo Hsiung Lee,Kuo Hsiung Lee,Lan Xie +14 more
TL;DR: Computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant, as well as good balance between anti-HIV-1 activity and desirable druglike properties.
Journal ArticleDOI
Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.
Walid A. M. Elgaher,Kamal Kant Sharma,Jörg Haupenthal,Francesco Saladini,Manuel Pires,Eleonore Real,Yves Mély,Rolf W. Hartmann +7 more
TL;DR: The novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains, and mode of action studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp.
Journal ArticleDOI
Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X(7) receptor.
Lee Abberley,Aude Bebius,Paul John Beswick,Andy Billinton,Katharine Laura Collis,David Kenneth Dean,Elena Fonfria,Robert Gleave,Stephen J. Medhurst,Anton D. Michel,Andrew P. Moses,Sadhana Patel,Shilina Roman,Tiziana Scoccitti,Beverley Smith,Jon Graham Anthony Steadman,Daryl S. Walter +16 more
TL;DR: A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule, and compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability.
Journal ArticleDOI
Discovery of small molecule human FPR1 receptor antagonists.
Hitesh J. Sanganee,Andrew Baxter,Simon Barber,Alastair J. H. Brown,Denise Grice,Fraser Hunt,Sarah King,David Laughton,Garry Pairaudeau,Bob Thong,Richard J. Weaver,John Unitt +11 more
TL;DR: The identification of two novel series of formyl peptide receptor 1 (FPR1) antagonists are reported, represented by methionine benzimidazole 6 and diamide 7, making them useful in vitro validation tools for the target.
Journal ArticleDOI
Understanding the molecular properties and metabolism of top prescribed drugs.
TL;DR: The data show that addition of hydrochloride is the most common method to increase solubility of drug ingredients and Cytochrome P450 isozymes 3A4, 2D6, 2C9,2C8 and 3C5 are the top five proteins that metabolize the 200 most prescribed drugs.
References
More filters
Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Journal ArticleDOI
Molecular properties that influence the oral bioavailability of drug candidates.
Daniel F. Veber,Stephen R. Johnson,Hung-Yuan Cheng,Brian R. Smith,Keith W. Ward,Kenneth D. Kopple +5 more
TL;DR: Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count are found to be important predictors of good oral bioavailability, independent of molecular weight.
Journal ArticleDOI
Can the pharmaceutical industry reduce attrition rates
Ismail Kola,John Landis +1 more
TL;DR: The pharmaceutical industry faces considerable challenges, both politically and fiscally, and the fiscal pressures that face the industry from the perspective of R&D are dealt with.
Book
The Merck index
TL;DR: This CD-ROM provides the tools to draw structures and then search for them, and presents over 10,000 monographs which detail chemicals, drugs and biologicals, and describe a single substance or small group of related compounds.
Journal ArticleDOI
Lead- and drug-like compounds: the rule-of-five revolution.
TL;DR: This topic is explored in terms ofDrug-like physicochemical features, drug-like structural features, a comparison of drug- like and non-drug-like in drug discovery and a discussion of how drug-Like features relate to clinical success.