ABSTRACT
GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic ß-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.
Subject(s)
Benzamides/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/therapeutic use , Piperidines/therapeutic use , Receptors, G-Protein-Coupled/agonists , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , CHO Cells , Cricetulus , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Mice, Inbred ICR , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.
Subject(s)
Drug Design , Proto-Oncogene Proteins/antagonists & inhibitors , Repressor Proteins/antagonists & inhibitors , Amines/chemistry , Amines/metabolism , Amines/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme-Linked Immunosorbent Assay , HEK293 Cells , Half-Life , High-Throughput Screening Assays , Humans , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Protein Binding , Protein Interaction Maps , Protein Structure, Tertiary , Proto-Oncogene Proteins/metabolism , Repressor Proteins/metabolism , Two-Hybrid System TechniquesABSTRACT
We previously reported a facile preparation method of 3-substituted-2,6-difluoropyridines, which were easily converted to 2,3,6-trisubstituted pyridines by nucleophilic aromatic substitution with good regioselectivity and yield. In this study, we demonstrate the synthetic utility of 3-substituted-2,6-difluoropyridines in drug discovery via their application in the synthesis of various 2,3,6-trisubstituted pyridines, including macrocyclic derivatives, as novel protein kinase C theta inhibitors in a moderate to good yield. This synthetic approach is useful for the preparation of 2,3,6-trisubstituted pyridines, which are a popular scaffold for drug candidates and biologically attractive compounds.
Subject(s)
Isoenzymes/antagonists & inhibitors , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemistry , Drug Design , Humans , Isoenzymes/metabolism , Protein Kinase C/metabolism , Protein Kinase C-theta , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesisABSTRACT
An efficient synthesis of (2S,3R)-3-hydroxy-3-methylproline (OHMePro), a component of polyoxypeptins, and relatives was achieved, in which an intramolecular asymmetric aldol reaction of the ketoaldehyde using OHMePro itself as an organocatalyst constitutes a key step.
