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.
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.
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: hideyuki.igawa@takeda.com.
Hideyuki
H
Igawa
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Masashi
M
Takahashi
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Minoru
M
Ikoma
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Hiromi
H
Kaku
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Keiko
K
Kakegawa
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Asato
A
Kina
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Jumpei
J
Aida
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Shoki
S
Okuda
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Yayoi
Y
Kawata
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Toshihiro
T
Noguchi
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Natsu
N
Hotta
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Syunsuke
S
Yamamoto
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Masaharu
M
Nakayama
CVM Marketing Japan Pharma Business Unit, Takeda Pharmaceutical Co., Ltd, 12-10, Nihonbashi 2-Chome, Chuo-ku, Tokyo 103-8686, Japan.
Yasutaka
Y
Nagisa
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Shizuo
S
Kasai
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Tsuyoshi
T
Maekawa
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D007191:Indazoles; C103263:MCHR1 protein, human; C491208:MCHR1 protein, rat; D011728:Pyridones; D017481:Receptors, Somatostatin
Ames test; Antiobesity agent; DNA intercalator; Indazole; MCH; MCHR1 antagonist; Mutagenicity