Abstract
We describe here the generation of a lead compound and its optimization studies that led to the identification of a novel GPR119 agonist. Based on a spirocyclic cyclohexane structure reported in our previous work, we identified compound 8 as a lead compound, being guided by ligand-lipophilicity efficiency (LLE), which linked potency and lipophilicity. Subsequent optimization studies of 8 for improvement of solubility afforded representative 21. Compound 21 had no inhibitory activity against six CYP isoforms and showed favorable pharmacokinetic properties and hypoglycemic activity in rats.
Keywords:
GPR119 agonist; Spirocyclic structure.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
-
Animals
-
Cyclohexanes / chemical synthesis
-
Cyclohexanes / chemistry
-
Cyclohexanes / pharmacology*
-
Cytochrome P-450 Enzyme Inhibitors / chemical synthesis
-
Cytochrome P-450 Enzyme Inhibitors / chemistry
-
Cytochrome P-450 Enzyme Inhibitors / pharmacology*
-
Cytochrome P-450 Enzyme System / metabolism
-
Dose-Response Relationship, Drug
-
Humans
-
Hypoglycemic Agents / chemical synthesis
-
Hypoglycemic Agents / chemistry
-
Hypoglycemic Agents / pharmacology*
-
Ligands
-
Microsomes, Liver / chemistry
-
Microsomes, Liver / metabolism
-
Molecular Structure
-
Rats
-
Rats, Sprague-Dawley
-
Receptors, G-Protein-Coupled / agonists*
-
Receptors, G-Protein-Coupled / metabolism
-
Spiro Compounds / chemical synthesis
-
Spiro Compounds / chemistry
-
Spiro Compounds / pharmacology*
-
Structure-Activity Relationship
Substances
-
Cyclohexanes
-
Cytochrome P-450 Enzyme Inhibitors
-
GPR119 protein, rat
-
Hypoglycemic Agents
-
Ligands
-
Receptors, G-Protein-Coupled
-
Spiro Compounds
-
Cytochrome P-450 Enzyme System