Back to Search
Start Over
Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test
- Source :
- Bioorganic & Medicinal Chemistry. 24:2504-2518
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50=35nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9- condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile.
- Subjects :
- Male
0301 basic medicine
Benzimidazole
Imidazopyridine
Indazoles
Pyridones
Stereochemistry
Clinical Biochemistry
Pharmaceutical Science
01 natural sciences
Biochemistry
Ames test
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Drug Discovery
Animals
Humans
Obesity
Receptors, Somatostatin
Molecular Biology
Indazole
Trifluoromethyl
Dose-Response Relationship, Drug
Molecular Structure
Bicyclic molecule
010405 organic chemistry
Organic Chemistry
Rats, Inbred F344
Rats
0104 chemical sciences
Melanin-concentrating hormone receptor
030104 developmental biology
chemistry
Molecular Medicine
Amine gas treating
Anti-Obesity Agents
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....6f9eb52a0abcb2500d12f70c46b64239