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Synthesis, structure-activity relationship, and pharmacological studies of novel melanin-concentrating hormone receptor 1 antagonists 3-aminomethylquinolines: reducing human ether-a-go-go-related gene (hERG) associated liabilities
- Source :
- Journal of medicinal chemistry. 55(9)
- Publication Year :
- 2012
-
Abstract
- Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.
- Subjects :
- Spectrometry, Mass, Electrospray Ionization
Magnetic Resonance Spectroscopy
Stereochemistry
hERG
CHO Cells
Pharmacology
Molecular Dynamics Simulation
Ligands
chemistry.chemical_compound
Inhibitory Concentration 50
Structure-Activity Relationship
Cricetinae
Drug Discovery
Structure–activity relationship
Animals
Humans
Obesity
Receptors, Pituitary Hormone
Receptor
Benzamide
biology
Chemistry
Quinoline
Antagonist
Stereoisomerism
Ether-A-Go-Go Potassium Channels
Rats, Inbred F344
Melanin-concentrating hormone receptor
Rats
Docking (molecular)
Benzamides
biology.protein
Quinolines
Molecular Medicine
Anti-Obesity Agents
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 55
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....75eacf4488a6edf24b9ddbd87d5eccc0