ABSTRACT
Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.
ABSTRACT
The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
Subject(s)
Hypoglycemic Agents/chemical synthesis , PPAR alpha/agonists , PPAR gamma/agonists , Pyrrolidines/chemistry , Animals , Blood Glucose/analysis , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Female , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Ligands , Mice , Mice, Obese , PPAR alpha/metabolism , PPAR gamma/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/therapeutic use , Stereoisomerism , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.
Subject(s)
Drug Discovery , Heterocyclic Compounds, 3-Ring/pharmacology , Receptors, Glucocorticoid/agonists , Thiadiazoles/pharmacology , Urea/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemistry , Urea/analogs & derivatives , Urea/chemistryABSTRACT
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.
Subject(s)
Amides/chemistry , Amides/pharmacology , Drug Discovery , Receptors, Glucocorticoid/agonists , Binding Sites , Crystallography, X-Ray , Humans , Indazoles/chemistry , Indazoles/pharmacology , Molecular Structure , Protein Binding/drug effects , Steroids/chemistry , Steroids/pharmacology , Structure-Activity RelationshipABSTRACT
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.
Subject(s)
Indazoles/chemical synthesis , Indazoles/pharmacology , Receptors, Glucocorticoid/agonists , Amides/chemistry , Amides/pharmacology , Humans , Indazoles/chemistry , Models, Molecular , Protein Binding/drug effects , Receptors, Glucocorticoid/chemistry , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Urea/chemistry , Urea/pharmacologyABSTRACT
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38ß isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Binding Sites , Crystallography, X-Ray , Humans , Hydrogen Bonding , Mitogen-Activated Protein Kinase 14/metabolism , Molecular Dynamics Simulation , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptors, Glucocorticoid/agonists , Thiadiazoles/chemical synthesis , Alkaline Phosphatase/biosynthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Cell Line, Tumor , Drug Partial Agonism , Edema/drug therapy , Glutamate-Ammonia Ligase/biosynthesis , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , In Vitro Techniques , Interleukin-1beta/blood , Male , Models, Molecular , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Response Elements , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Transcriptional Activation , Tumor Necrosis Factor-alpha/blood , Tyrosine Transaminase/biosynthesisABSTRACT
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Subject(s)
Anti-Inflammatory Agents/chemistry , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrroles/chemistry , Triazines/chemistry , Administration, Oral , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Binding Sites , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Mice , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Rats , Structure-Activity Relationship , Triazines/pharmacology , Triazines/therapeutic useABSTRACT
A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.
Subject(s)
Amides/pharmacology , Receptors, Glucocorticoid/agonists , Amides/chemistry , Animals , Models, Molecular , RatsABSTRACT
The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.
Subject(s)
Mitogen-Activated Protein Kinase 14/chemistry , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/pharmacology , Animals , Crystallography, X-Ray , Mice , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyrroles/chemical synthesis , Triazines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Biological Availability , Caco-2 Cells , Crystallography, X-Ray , Female , Humans , Hydrogen Bonding , In Vitro Techniques , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred BALB C , Microsomes, Liver/metabolism , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Molecular Conformation , Protein Binding , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Triazines/pharmacokinetics , Triazines/pharmacology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The design, synthesis, and structure-activity relationships (SAR) of a series of 2-aminothiazol-5-yl-pyrimidines as novel p38α MAP kinase inhibitors are described. These efforts led to the identification of 41 as a potent p38α inhibitor that utilizes a unique nitrogen-sulfur intramolecular nonbonding interaction to stabilize the conformation required for binding to the p38α active site. X-ray crystallographic studies that confirm the proposed binding mode of this class of inhibitors in p38 α and provide evidence for the proposed intramolecular nitrogen-sulfur interaction are discussed.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Nitrogen/chemistry , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemistry , Sulfur/chemistry , Thiazoles/chemistry , Binding Sites , Crystallography, X-Ray , Drug Design , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
Subject(s)
Anthracenes/pharmacology , Drug Discovery , Receptors, Glucocorticoid/metabolism , Anthracenes/chemistry , Cell Line , Crystallography, X-Ray , Drug Discovery/methods , Glucocorticoids/chemistry , Glucocorticoids/pharmacology , Humans , Protein Binding/drug effects , Protein Binding/physiology , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/physiology , Structure-Activity RelationshipABSTRACT
The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.
Subject(s)
Azoles/chemical synthesis , Drug Design , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Azoles/pharmacology , Cell Line/enzymology , Crystallography, X-Ray , Female , Humans , Hydrogen-Ion Concentration , Mice , Mice, Transgenic , PPAR alpha/metabolism , PPAR gamma/metabolism , Structure-Activity RelationshipABSTRACT
Humankind has been in the business of discovering drugs for thousands of years. At present, small-molecule drug design is based on specific macromolecular receptors as targets for inhibition or modulation. To this end, a number of clever approaches have evolved over time: computer-aided techniques including structure-activity relationships and synthesis, high-throughput screening, quantitative structure-activity relationships, hypotheses derived from ligand- and/or structure-based information and focused library approaches. In recent years, several alternative strategies have appeared in the form of the emerging paradigms of polypharmacology, systems biology and personalized medicine. These innovations point to key challenges and breakthroughs likely to affect the future of small-molecule drug discovery.
Subject(s)
Drug Discovery/methods , Drug Discovery/trends , Clinical Trials as Topic , Computer-Aided Design , Humans , Medicine, Traditional , Molecular Structure , Plant Extracts/chemistry , Precision Medicine , Small Molecule Libraries , Structure-Activity Relationship , Systems BiologyABSTRACT
The concept of quantitative SAR (QSAR) is inherently imbued with an expectation of predictivity, novel insights and the generation of useful hypotheses, particularly as applied to the drug discovery process. However, even recently developed QSAR models often appear to be flawed, characterized by mediocre predictive power and undecipherable descriptors. As a result, users may be able to derive only a vague notion of which molecular features are correlated to activity. Consideration of several precautions is necessary to attempt to circumvent the misuse and misunderstanding of the QSAR technique. Issues related with QSAR include an erroneous association of correlation with causation, the close relationship between large numbers of descriptors and the effect of chance factor, the misuse of the 'leave-one-out' paradigm, and finally, the QSAR enigma, wherein the predictivity of a model is not necessarily a measure of a model's utility.
Subject(s)
Drug Design , Pharmacology, Clinical/trends , Quantitative Structure-Activity Relationship , Computational Biology , Pharmaceutical Preparations/chemistry , Research , Subject HeadingsABSTRACT
A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38 alpha enzyme.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemistry , Triazines/chemical synthesis , Triazines/pharmacology , Amides/chemistry , Animals , Crystallography, X-Ray , Female , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Triazines/chemistry , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation.
Subject(s)
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Thiazoles/pharmacology , Animals , Arthritis/drug therapy , Caco-2 Cells , Cell Membrane Permeability/drug effects , Cells, Cultured , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Lipopolysaccharides/pharmacology , Male , Mice , Microsomes, Liver/drug effects , Mitogen-Activated Protein Kinase 14/metabolism , Molecular Structure , Monocytes/cytology , Monocytes/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Inbred Lew , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.