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

[Display omitted] 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. T...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2016-06, Vol.24 (11), p.2504-2518
Main Authors: Igawa, Hideyuki, Takahashi, Masashi, Ikoma, Minoru, Kaku, Hiromi, Kakegawa, Keiko, Kina, Asato, Aida, Jumpei, Okuda, Shoki, Kawata, Yayoi, Noguchi, Toshihiro, Hotta, Natsu, Yamamoto, Syunsuke, Nakayama, Masaharu, Nagisa, Yasutaka, Kasai, Shizuo, Maekawa, Tsuyoshi
Format: Article
Language:English
Subjects:
Ames test
Animals
Anti-Obesity Agents - chemical synthesis
Anti-Obesity Agents - chemistry
Anti-Obesity Agents - pharmacology
Antiobesity agent
DNA intercalator
Dose-Response Relationship, Drug
Humans
Indazole
Indazoles - chemical synthesis
Indazoles - chemistry
Indazoles - pharmacology
Male
MCH
MCHR1 antagonist
Molecular Structure
Mutagenicity
Obesity - drug therapy
Pyridones - chemical synthesis
Pyridones - chemistry
Pyridones - pharmacology
Rats
Rats, Inbred F344
Receptors, Somatostatin - antagonists & inhibitors
Structure-Activity Relationship
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.04.013