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Lead generation and optimization of novel GPR119 agonists with a spirocyclic cyclohexane structure.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Feb 01; Vol. 29 (3), pp. 373-379. Date of Electronic Publication: 2018 Dec 18. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cyclohexanes chemical synthesis
Cyclohexanes chemistry
Cytochrome P-450 Enzyme Inhibitors chemical synthesis
Cytochrome P-450 Enzyme Inhibitors chemistry
Cytochrome P-450 Enzyme System metabolism
Dose-Response Relationship, Drug
Humans
Hypoglycemic Agents chemical synthesis
Hypoglycemic Agents chemistry
Ligands
Microsomes, Liver chemistry
Microsomes, Liver metabolism
Molecular Structure
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled metabolism
Spiro Compounds chemical synthesis
Spiro Compounds chemistry
Structure-Activity Relationship
Cyclohexanes pharmacology
Cytochrome P-450 Enzyme Inhibitors pharmacology
Hypoglycemic Agents pharmacology
Receptors, G-Protein-Coupled agonists
Spiro Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30587450
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.12.041