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
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.
Subject(s)
Drug Discovery , Glycine/analogs & derivatives , Oxazoles/chemistry , Oxazoles/pharmacology , PPAR alpha/agonists , Animals , Cell Line , Cricetinae , Crystallography, X-Ray , Drug-Related Side Effects and Adverse Reactions , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Glycine/toxicity , Humans , Male , Mice , Models, Molecular , Oxazoles/chemical synthesis , Oxazoles/toxicity , PPAR alpha/chemistry , PPAR alpha/genetics , Protein Structure, Tertiary , Substrate Specificity , Transcriptional Activation/drug effectsABSTRACT
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
Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARalpha/gamma agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the alpha,beta-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.
Subject(s)
Carboxylic Acids , PPAR alpha/agonists , PPAR gamma/agonists , Piperidines , Binding, Competitive/drug effects , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
Subject(s)
Amino Acids/pharmacology , Molecular Mimicry , Phenyl Ethers/pharmacology , Phenylacetates/pharmacology , Receptors, Thyroid Hormone/drug effects , Amino Acids/chemistry , Animals , CHO Cells , Cholesterol, Dietary/administration & dosage , Cricetinae , Cricetulus , Ligands , Radioligand Assay , Rats , Receptors, Thyroid Hormone/metabolismABSTRACT
A novel series of potent dual agonists of PPARalpha and PPARgamma, the alkoxybenzylglycines, was identified and explored using a solution-phase library approach. The synthesis and structure-activity relationships of this series of dual PPARalpha/gamma agonists are described.
Subject(s)
Glycine/analogs & derivatives , Glycine/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Amino Acids/chemistry , Amino Acids/pharmacology , Animals , Blood Glucose/drug effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Mice , Mice, Inbred Strains , Structure-Activity RelationshipABSTRACT
High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.
Subject(s)
Naphthalenes/chemistry , Receptors, Thyroid Hormone/metabolism , Thyroid Hormones/metabolism , Models, Molecular , Structure-Activity Relationship , Thyroid Hormones/chemistryABSTRACT
Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.
Subject(s)
Glycine/analogs & derivatives , Glycine/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Oxazoles/chemical synthesis , PPAR alpha/agonists , PPAR gamma/agonists , Adipocytes/cytology , Animals , Blood Glucose/drug effects , Cell Line , Diabetes Mellitus, Type 2/drug therapy , Fatty Acids/blood , Glycine/chemistry , Glycine/pharmacology , Humans , Hyperlipidemias/drug therapy , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Insulin/blood , Male , Mice , Mice, Obese , Oxazoles/chemistry , Oxazoles/pharmacology , Transcriptional Activation , Triglycerides/bloodABSTRACT
A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity.
