ABSTRACT
With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.
Subject(s)
Pyrroles , Animals , Rats , Structure-Activity Relationship , Humans , Molecular Structure , Pyrroles/pharmacology , Pyrroles/chemistry , Pyrroles/chemical synthesis , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/chemistry , Dose-Response Relationship, Drug , Drug Discovery , Male , Rats, Sprague-Dawley , Receptors, SomatostatinABSTRACT
A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable in vitro profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight. Subsequent studies in MGAT2 knockout mice with the lead candidate 12 (BMS-986172) showed on-target- and mechanism-based pharmacology. Moreover, its favorable pharmacokinetic (PK) profile and the lack of species variability in the glucuronidation potential resulted in a greater confidence level in the projection of a low dose for achieving targeted efficacious exposures in humans. Consistent with these projections, PK data from a phase 1 trial confirmed that targeted efficacious exposures could be achieved at a low dose in humans, which supported compound 12 as our second and potentially superior development candidate for the treatment of various metabolic disorders.
Subject(s)
Metabolic Diseases , Pyridones , Animals , Humans , Mice , Body Weight , Metabolic Diseases/drug therapy , Pyridones/chemistry , Pyridones/pharmacology , N-Acetylglucosaminyltransferases/antagonists & inhibitorsABSTRACT
Inhibition of monoacylglycerol transferase 2 (MGAT2) has recently emerged as a potential therapeutic strategy for the treatment of metabolic diseases such as obesity, diabetes and non-alcoholic steatohepatitis (NASH). Metabolism studies with our clinical lead (1) suggested variability in in vitro glucuronidation rates in liver microsomes across species, which made projection of human doses challenging. In addition, the observation of deconjugation of the C3-C4 double bond in the dihydropyridinone ring of 1 in solution had the potential to complicate its clinical development. This report describes our lead optimization efforts in a novel pyridinone series, exemplified by compound 33, which successfully addressed both of these potential issues.
Subject(s)
Metabolic Diseases , Monoglycerides , Humans , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/chemistry , Obesity/drug therapy , Metabolic Diseases/drug therapyABSTRACT
GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs.
Subject(s)
Blood Glucose , Hyperglycemia , Rats , Animals , Receptors, G-Protein-Coupled , Glucagon-Like Peptide 1 , Hypoglycemic Agents/pharmacology , Pyrrolidines/pharmacology , Pyrrolidines/chemistry , InsulinABSTRACT
The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).
Subject(s)
Drug Discovery , Pulmonary Fibrosis/drug therapy , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Male , Mice , Molecular Structure , Pulmonary Fibrosis/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Lysophosphatidic Acid/metabolism , Structure-Activity RelationshipABSTRACT
MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays/methods , Metabolic Diseases/drug therapy , N-Acetylglucosaminyltransferases/antagonists & inhibitors , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Structure-Activity RelationshipABSTRACT
G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
Subject(s)
Drug Discovery , Pyrazoles/pharmacology , Pyrazoles/pharmacokinetics , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Biological Availability , Humans , Male , Mice , Models, Molecular , Molecular Conformation , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrrolidines/chemistryABSTRACT
BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.
ABSTRACT
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
Subject(s)
Arginine/analogs & derivatives , Flavones/chemistry , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Animals , Arginine/chemical synthesis , Arginine/chemistry , Arginine/pharmacology , Brain/metabolism , Caco-2 Cells , Cell Membrane Permeability , Feeding Behavior/drug effects , Flavones/chemical synthesis , Flavones/pharmacology , HEK293 Cells , Humans , Male , Membranes, Artificial , Mice, Knockout , Microsomes, Liver/metabolism , Mutation , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/genetics , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics , Serotonin 5-HT2 Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Azetidines/pharmacology , Enzyme Inhibitors/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Actins/antagonists & inhibitors , Adamantane/administration & dosage , Adamantane/chemistry , Adamantane/pharmacology , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Biological Availability , Crystallography, X-Ray , Dogs , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Female , Half-Life , Humans , Hypothalamo-Hypophyseal System/drug effects , Inhibitory Concentration 50 , Macaca fascicularis , Male , Mice, Obese , Rats , Structure-Activity RelationshipABSTRACT
A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
Subject(s)
Hypoglycemic Agents/pharmacology , Pyrrolidines/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Cell Line , Cells, Cultured , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glucagon-Like Peptide 1/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Male , Mice, Inbred C57BL , Models, Molecular , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/therapeutic use , Rats , Receptors, G-Protein-Coupled/metabolismABSTRACT
The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.
Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/therapeutic use , Obesity/drug therapy , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Dogs , Halogenation , Humans , Macaca fascicularis , Male , Mice , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.
Subject(s)
Brain/drug effects , Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Triazines/pharmacology , Animals , Brain/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Obesity/metabolism , Rats , Structure-Activity Relationship , Triazines/administration & dosage , Triazines/chemistryABSTRACT
Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.
Subject(s)
Anti-Obesity Agents/chemistry , Pyrazoles/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Half-Life , Humans , Obesity/drug therapy , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Weight Loss/drug effectsABSTRACT
A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11ß-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Metabolic Diseases/drug therapy , Sulfonamides/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Binding Sites , Drug Evaluation, Preclinical , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Humans , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/therapeutic useABSTRACT
G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic ß-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.
Subject(s)
Drug Discovery , Hypoglycemic Agents/pharmacology , Molecular Targeted Therapy , Pyridones/pharmacology , Receptors, G-Protein-Coupled/metabolism , Sulfones/pharmacology , Animals , Clinical Trials as Topic , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Design , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Male , Mice , Models, Molecular , Protein Conformation , Pyridones/chemistry , Pyridones/pharmacokinetics , Pyridones/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/chemistry , Sulfones/chemistry , Sulfones/pharmacokinetics , Sulfones/therapeutic useABSTRACT
Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).
Subject(s)
Anti-Obesity Agents/pharmacology , Drug Discovery , Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/therapeutic use , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Male , RatsABSTRACT
Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase-type 1 (11ß-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11ß-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.
ABSTRACT
Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.
Subject(s)
Benzofurans/pharmacology , Receptors, G-Protein-Coupled/agonists , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cell Line , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11ß-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11ß-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11ß-HSD1 with a favorable development profile.