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Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition
- Source :
- Bioorganic & Medicinal Chemistry. 24:2486-2503
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1 H )-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2- a ]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1 H )-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1 H -benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1 . Optimization of 6a afforded a series of potent thiophene derivatives ( 6q – u ); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF 3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1 H -benzimidazol-6-yl)pyridin-2(1 H )-one ( 6s ) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats.
- Subjects :
- Male
0301 basic medicine
Imidazopyridine
Benzimidazole
Time Factors
Pyridones
Stereochemistry
Clinical Biochemistry
Pharmaceutical Science
Biochemistry
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Drug Discovery
Thiophene
Animals
Cytochrome P-450 CYP3A
Humans
HATU
Obesity
Receptors, Somatostatin
Molecular Biology
Dose-Response Relationship, Drug
Molecular Structure
Bicyclic molecule
Organic Chemistry
Sulfoxide
Rats, Inbred F344
Rats
Melanin-concentrating hormone receptor
030104 developmental biology
chemistry
Drug Design
Molecular Medicine
Benzimidazoles
Anti-Obesity Agents
Lead compound
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....fbada861a07cfc93c3c995d6e8118a2e