ABSTRACT
A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.
Subject(s)
Blood Glucose/drug effects , Drug Discovery , Oximes/chemical synthesis , Propane/analogs & derivatives , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Inhibitory Concentration 50 , Mice , Molecular Structure , Oximes/chemistry , Oximes/pharmacology , Propane/blood , Propane/chemical synthesis , Propane/chemistry , Propane/pharmacologyABSTRACT
Potency with potential: 2-Phenoxy-nicotinamides were identified as potent agonists at the GPBAR1 receptor, a target in the treatment of obesity, type 2 diabetes and metabolic syndrome. Extensive structure-activity relationship studies supported by homology modeling and docking resulted in the identification of optimized GPBAR1 agonists, potent against both human and mouse receptors, endowed with favorable physicochemical properties and good metabolic stability.
Subject(s)
Niacinamide/chemistry , Receptors, G-Protein-Coupled/agonists , Binding Sites , Humans , Molecular Docking Simulation , Niacinamide/metabolism , Protein Binding , Protein Structure, Tertiary , Quinolines/chemistry , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
Subject(s)
Benzimidazoles/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , para-Aminobenzoates , 4-Aminobenzoic Acid/chemical synthesis , 4-Aminobenzoic Acid/chemistry , 4-Aminobenzoic Acid/pharmacokinetics , Administration, Oral , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Binding Sites , Computer Simulation , Crystallography, X-Ray , Humans , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Molecular Conformation , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, LDL/deficiency , Receptors, LDL/genetics , Receptors, LDL/metabolism , Structure-Activity RelationshipABSTRACT
Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.
Subject(s)
Hypoglycemic Agents/chemistry , Hypolipidemic Agents/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Administration, Oral , Animals , Binding Sites , Computer Simulation , Diabetes Mellitus, Experimental/drug therapy , Drug Evaluation, Preclinical , Dyslipidemias/drug therapy , Hypoglycemic Agents/administration & dosage , Hypolipidemic Agents/administration & dosage , Mice , Mice, Knockout , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Structure-Activity RelationshipABSTRACT
Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.
