Showing papers in "Current Medicinal Chemistry in 1994"

ACAT inhibitors: potential anti-atherosclerotic agents

Abstract: The evolution of ACAT inhibitors •from purely hypocholestero­ lemic agents to potential anti-atherosclerdtic agents has occurred only recently.A large number of structurally diverse ACAT inhibitors were initially developed as hypocholesterolemic agets whose prime mechanism of action was inhibition of dietary cholesterol absorption in the intestine, however, efficacy for such non-absorbable agents, in humans, has remained elusive. Esterification of cholesterol within the hepatocyte has been shown to be required for VLDL synthesis and secretion, and inhibition of ACAT within the artery wall may prove to be the \"ultimate\" anti-atherosclerotic mechanism by preventing the formation of cholesterol ester loaded macrophages (foam cells), the precursors of the fatty streak, an early lesion in the atherosclerotic process. Thus, more recently, there has been a concerted effort to design more bioavailable inhibitors capable of inhibiting the enzyme in the liver and artery wall. Displaying direct efficacy at the artery wall for an ACAT inhibitor has been complicated by the fact that in pre-clinical animal models, it has been difficult to dissociate the effects of lipid lowering from a true direct effect at the artery wall. Recently, a novel ACAT inhibitor, Cl-976, has been disclosed which displays anti-atherosclerotic activity in an injured cholesterol fed rabbit model of atherosclerosis without exhibiting a cholesterol lowering effect.The SAR around Cl-976 and related series will be discussed and placed in context with other novel structural types of ACAT inhibitors appearing in the recent literature.

The medicinal chemistry of nonsteroidal antiestrogens: a review

Abstract: The inhibition of estrogen is a particularly useful strategy for the treatment of hormone-dependent breast tumors in postmenopausal females and possibly in premenopausal women and as a chemosuppressive in women at high risk of developing breast cancer. Nonsteroidal antiestrogens which exhibit potent antitumor effects represent a major advance in the management of breast cancer. Considerable effort by many research groups has been devoted to the search for novel pure nonsteroidal antiestrogens with the hope of finding antitumor agents that would be useful in estrogen receptor (ER) positive or estrogen receptor (ER) negative disease. The reasoning behind the search for pure antiestrogens is based on the recognition that antiestrogens generally possess the partial estrogenic activity and a complete blockade of estrogen action cannot be achieved by agents like tamoxifen. Novel pure antiestrogens should be more effective than partial agonist in reducing the mitogenic action of estrogen on the growth of breast tumors and complete ablation of hormonal-dependent tumor growth is very desirable since it could provide a more rapid and longer-lasting remission. In addition, pure antiestrogens could be more effective in patients who experience a relapse during tamoxifen therapy, serving as a second-line treatment, and have the potential of demonstrating greater efficacy in first-line treatment of advanced breast cancer. This review covers the chemistry of the experimental and potentially useful nonsteroidal antiestrogens and the only agent, tamoxifen, used in the therapy of breast cancer with special emphasis on structure-activity relationships. Special attention was paid to the structural classes [1,2-bis(hydroxyphenyl)ethane; 2-phenylindoles; indolo[2,1-a] isoquinolines; 2-phenylbenzo[b] thiophenes; dibenzo[a,g]quinolizinones; triarylpropenones (TAPs); 3,4-dihydro-1-naphthalenyl­ methanones; 3-aroyl-2-arylbenzo[b]thiophenes; 2,3-diaryi-2H-1-benzopyrans; triphenyl­ ethylenes (TPEs); dichlorodiarylcyclopropanes (DDACs) and the 1,1-dichloro-2,2,3-triarylcyclo­ propanes (DTACs)] whose agents demonstrated particular activity in the in vitro receptor binding affinity assay and the in vivo uterotrophic and antiuterotrophic assays. Where possible, the in vitro antiproliferative properties of these agents in cell culture assays also were discussed.

Anticonvulsant enaminones: with emphasis on methyl 4-[(p-chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-en-1-oate (ADD 196022)

Abstract: Enaminones, enamines of B-dicarbonyl compounds have been known for many years. Their main therapeutic utility was as prodrugs for various amines, stabilizing these active compounds principally in basic media. Our laboratory discovered a series of enamines of cyclic 1,3-diketo esters which were stable and possessed significant anticonvulsant activity. The most notable compound was methyl 4- [(p­ chlorophenyl)amino)-6-methyl-2-oxocyclohex-3-en-1-oate, 15, desig­ nated ADD 196022 by the Anti-convulsant Drug Development (ADD) Program of the National Institutes of Health. Compound 15 displayed an intraperitoneal (ip) EDso of 26.2 mg/kg and a TDso of 254.8 mg/kg in the mouse and an oral (po) EDso of 5.8 mg/kg and a TDso of >380 mg/kg in the rat. The protective indices (TDso/EDso) were 9.7 in the mouse and >65.6 in the rat, respectively. This data compared favorably to phenytoin and carbamazepine. In addition, 15 demonstrated oral effectiveness in the rat corneal kindling model, providing an EDso of 34.2 mg/kg. Quantitative structure-activity studies in this series successfully utilized the Craig Plot method (Craig, P. N.J. Med Chern. 1971, 14, 680; Craig, P. N.J. Med Chern. 1972, 15, 144). High field NMR , molecular modeling studies and CLOGP were also employed to assess the potential interactions of these compounds and phenytoin in its relationship to potential anticonvulsant activity. Each of these factors is discussed.

Inositol analogs as potential anticancer therapeutics

Abstract: The myo-inositol pathway is an attractive target for the control of cellular proliferation. Compounds which interfere with this pathway are potential targets for anticancer drug development. Chemical derivatives of selected intermediates along this pathway were constructed, including analogs of inositol, phosphatidylinositol and inositol phosphates. These compounds were tested for their ability to effect metabolic regulation, intracellular Ca2+ release, as well as cellular trafficking. A number of these compounds were found to inhibit cell growth. The myo-inositol pathway as well as the biological activity of these novel inositol analogs is reviewed.

Cholecystokinin receptor antagonists: current status

Abstract: Cholecystokinin (CCK), an endogenous peptide hormone, has been shown to have a wide range of physiological responses which has simulated a significant interest in identifying agonists and antagonists for CCK. Efforts, primarily led by the pharmaceutical industry, have led to the identification and development of CCK-A selective agents such as Loxiglumide and Devazepide. Both of these compounds have been evaluated in the clinic. More recently, due to the potential therapeutic utility of CCK-B antagonist in the treatment of anxiety, a large number of CCK-B receptor selective antagonists, such as L-365260 and Cl-988, have been identified and developed. This has resulted in extensive structure activity relationship studies on a wide-range of templates. This article will focus on the medicinal chemistry approaches, and SAR studies utilized by various laboratories to define the optimal template for both CCK-A and CCK-8 receptor selective antagonists.

Atypical antipsychotics based on the D2/5-HT2 ratio hypothesis

Abstract: Medicinal chemistry has played a major role in the improvement of antipsychotic therapy by helping to develop the 02/5-HT2 ratio hypothesis. Early pharmacological insights implicating a role for serotonin in schizophrenia by virtue of its control of the dopamine system have been tested by numerous combined 02/5-HT2 receptor antagonists. Recent work indicates that 5-HT2 receptor blockade can compensate for relatively weaker 02 receptor affinity, lessening the chance of side effects while maintaining antipsychotic efficacy. Many of the newer agents are poised to test the validity of the 02/5-HT2 ratio hypothesis in the clinic.

Development of agents to modulate the effects of endothelin

Abstract: Due partly to a greater understanding of the role of regulatory peptides and proteins in the pathophysiology of human disease there is considerable interest in designing agents that will modulate their effects. Endothelin-1 and its isopeptides belong to a family of novel vasoconstrictor agents first isolated from porcine aortic endothelial cells and subsequently found to be secreted from a variety of cell types. These peptides have potent biological effects on cardiovascular, renal, endocrine and neurological function. The rational design of receptor agonists and antagonists or proce­ ssing inhibitors from a ligand of interest, requires an understanding of the binding mode of the natural ligand(s) to the receptor(s) or enzyme and the relative importance of individual residues to binding. Screening of compound libraries and lead optimization techniques have also lead to pote'lt antagonists and processing enzyme inhibitors. This review will describe the progress achieved to date using both of these techniques to discover novel and potent endothelin agonists and antagonists of differing selectivity for the known ET receptor subtypes. Progress towards to design of endothelin converting enzyme inhibitors is also discussed. the discovery of agents to modulate the effects of endothelin will prove useful in elucidating the role of the endothelin family of peptides in human physiology and pathophysiology.

Protein-protein interactions as therapeutic targets for cancer

Abstract: The recent elucidation of many of the pathways involved in the regulation of cellular proliferation provides new opportunities for therapeutic intervention in the treatment of cancer. The inherent specificity of many of these protein-protein interactions should provide great selectivity, and emerging models of cell cycle control suggest that disrupting growth factor signalling pathways might selective_ly induce programmed cell death in cancer cells. However, many of these protein-protein interactions appear to occur over fairly large surfaces, suggesting that the identification of small molecules with the necessary affinity and specificity to disrupt these interactions in vivo represents a challenging undertaking. In the current review, we highlight three particular targets in the growth factor signalling pathways : growth factor - receptor binding, using Gastrin Releasing Peptide as a specific example; SH2 I SH3 domain interactions; and viral oncoprotein interaction with cellular proteins in the nucleus, focusing on the binding of Human Papillomavirus proteins with cellular growth suppressor gene products. These studies highlight both the promise and the pitfalls of selectively targeting protein-protein interactions for the treatment of cancer.

Non-peptide ligands for membrane-bound peptide receptors

Abstract: This article reviews some of the successful approaches made by medicinal chemists to discover non-peptide structures (peptide mimetics, peptidomimetics, peptoids) which act as agonists or antagonists at some of the membrane-bound receptors for endogenous peptides. Three fundamentally different strategies for the discovery of such ligands are discussed. Firstly, broad screening of as many compounds as possible from chemical databases to furnish an initial chemical lead which is subsequently modified to optimise biological activity. Secondly, a design strategy starting with the chemical structure of a known peptide antagonist or an endogenous agonist and modifying this into a non-peptide which incorporates elements of the peptide structure. Thirdly, a strategy of modifying the chemical structure of a previously reported non-peptide lead. These strategies are illustrated with examples of non­ peptide ligands for receptor subtypes of cholecystokinin (CCK), the neurokinins, the opioids, vasopressin, oxytocin, endothelin, angiotensin, neurotensin and bombesin.

Quinolone congeners as mammalian topoisomerase-II inhibitors

Abstract: The development of the quinolone antibacterials has clearly demonstrated that inhibition of topoisomerase activity can constitute an effective means by which to induce selective pathogen cell death. These agents disrupt normal bacterial gyrase protein-DNA substrate interactions and lead to the formation of a ternary \"cleavable complex\" which results in a bactericidp.l therapeutic mode of action. However, certain structural 'subsets' of quinolones have been shown to be toxic to mammalian cells as a result of competing inhibition of mammalian topoisomerase II activity. The investigation of these congeners has revealed that rather simple molecular modifications to the basic quinolone pharmacophore can potentiate activity against mammalian proteins. Structure-activity relationships have been elucidated in an attempt to selectively target the action of mammalian topoisomerase as a means for anticancer chemotherapy.

The biochemical disposition of methylenedioxyphenyl compounds

Abstract: This review summarizes the interactions of the methylene­ dioxyphenyl or benzodioxole function with cytochrome P450 and their toxicological and pharmacokinetic implications. The methylenedioxy group is a common group in natural and synth,etic medicinal compounds and provides an electronegative function that •is relatively unreactive and non polar. The function is oxidized by cytochrome P450 to form a catechol and T formate or carbon monooxide or alternatively, forms a complex with the heme iron of cytochrome P450. This complex, characterized by its absorption in the 455 nm range, can be very stable and inhibits the catalytic cycle of the enzyme. This inhibitory action has been used to enhance the actions of insecticides and has been the basis for pharmacokinetic drug interactions, The catechol product of benzodioxole ring cleavage is redox active and can participate in quinone­ reactive oxygen based toxicity. The chemical basis for these interactions are proposed together with experimental ob ervations reported in the recent literature. Examples of pharmacokinetic drug interactions are also included.

Progress towards selective inhibition of protein kinase C

Abstract: Protein kinase C (PKC), a member of the serine/threonine family of protein kinases, is an integral part of cellular signal transduction. There is mounting evidence that inappropriate activation of PKC may be responsible for a number of disease states. Potent, selective inhibitors of PKC could serve as valuable tools for def,lning these signaling pathways, as well as, for the treatment of diseases mediated through aberrant PKC activity. Several mechanistically-distinct classes of inhibitors have been identified which potently and selectively suppress PKC activity. The most advanced and promising of these agents are Go-6976 and Ro-32-0432, which arose from optimization studies on staurosporine, an indolecarbazole-based natural product. Though these compounds inhibit PKC competitively with respect to nucleotide cofactor, they exhibit little inhibitory activity against a range of other nucleotide-dependent enzymes. More modest advances have begun to be made with respect to selective inhibition of the various PKC isozymes. This review will update efforts directed towards the discovery of inhibitors of PKC, with a focus on the associated selectivity parameters.

Conformational studies of bioactive peptides by NMR

Abstract: Peptides are responsible for the regulation of a wide range of physiological functions. Their diverse biological roles, ranging from neurotransmitters to hormones, make them ideal targets for novel drug design. To utilize this potential it is necessary to determine the conformations of these potent bioactive molecules. Nuclear magnetic resonance spectroscopy provides a means for determining conformations of peptide species, both free in solution and, in appropriate cases, when bound to their receptors. In this article, NMR-based methods for determining conformations of bioactive peptides are described and illusrated with specific examples. This includes a discussion of qualitative and quantitative methods for assessment of NMR data, as well as methods used to investigate dynamics.