ABSTRACT
Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.
Subject(s)
Azetidines , Diabetes Mellitus, Type 2 , Hypoglycemia , Organophosphonates , Azetidines/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Glucokinase , Humans , Hypoglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Organophosphonates/pharmacology , Organophosphonates/therapeutic useABSTRACT
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzylamines/chemical synthesis , Benzylamines/pharmacology , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Animals , Anticholesteremic Agents/pharmacokinetics , Atherosclerosis/drug therapy , Benzamides/pharmacokinetics , Benzylamines/pharmacokinetics , Blood Pressure/drug effects , Cell Line , Cholesterol/metabolism , Cholesterol, HDL/blood , Cricetinae , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Dogs , Drug Discovery , Humans , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , Motor Activity/drug effects , Quinolines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
A G-Protein-coupled receptor-targeted library of aryloxypropanolamines and aryloxybutanolamines was efficiently executed using a novel, polymer-supported acyclic acetal linker, producing compounds in good yields and purities.
Subject(s)
Amines/chemical synthesis , Drug Design , Receptors, G-Protein-Coupled/antagonists & inhibitors , Small Molecule Libraries/chemical synthesis , Amines/pharmacology , Combinatorial Chemistry Techniques , Cross-Linking Reagents , Humans , Polymers , Propanolamines , Small Molecule Libraries/pharmacologyABSTRACT
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
Subject(s)
Lymphocyte Function-Associated Antigen-1/metabolism , Spiro Compounds/chemical synthesis , Thiophenes/chemical synthesis , Animals , Cell Adhesion/drug effects , Crystallography, X-Ray , Dogs , Graft Rejection/prevention & control , Humans , Lymphocyte Function-Associated Antigen-1/chemistry , Mice , Models, Molecular , Molecular Structure , Pneumonia/drug therapy , Pneumonia/immunology , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Transplantation, HomologousABSTRACT
A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
Subject(s)
Alanine/analogs & derivatives , Angiogenesis Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Triazines/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Alanine/chemical synthesis , Alanine/pharmacokinetics , Alanine/pharmacology , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Subject(s)
Amides/pharmacology , Anti-Inflammatory Agents/pharmacology , Enzyme Inhibitors/pharmacology , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Thiazoles/pharmacology , src-Family Kinases/antagonists & inhibitors , Administration, Oral , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Arthritis, Experimental/therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Male , Models, Molecular , Molecular Structure , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokineticsABSTRACT
A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro.
Subject(s)
Androgen Receptor Antagonists , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Hydantoins/chemical synthesis , Hydantoins/pharmacology , Aza Compounds/chemistry , Cell Line , Cell Survival/drug effects , Drug Design , Drug Evaluation, Preclinical , Evaluation Studies as Topic , Humans , Hydantoins/chemistry , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
We have previously disclosed the selective ET(A) receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ET(A) receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent leading to 16a (BMS-207940). Compound 16a is an extremely potent (ET(A) K(i) = 10 pM) and selective (80,000-fold for ET(A) vs ET(B)) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 micromol/kg, 16a displays enhanced duration relative to 1.
