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.
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(1H)-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(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-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 CF3 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-1H-benzimidazol-6-yl)pyridin-2(1H)-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.
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.
Mikio
M
Shirasaki
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.
Minoru
M
Ikoma
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Jumpei
J
Aida
CMC Center, Takeda Pharmaceutical Co., Ltd., 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan.
Tsuneo
T
Yasuma
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.
Syunsuke
S
Yamamoto
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Yasushi
Y
Fujioka
TCG Lifesciences Ltd., Block BN, Plot 7, Saltlake Electronics Complex, Sector V, Kolkata 700091, India.
Mrinalkanti
M
Kundu
TCG Lifesciences Ltd., Block BN, Plot 7, Saltlake Electronics Complex, Sector V, Kolkata 700091, India.
Uttam
U
Khamrai
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*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; 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; D013997:Time Factors
D019440:Anti-Obesity Agents; D001562:Benzimidazoles; C103263:MCHR1 protein, human; C491208:MCHR1 protein, rat; D011728:Pyridones; D017481:Receptors, Somatostatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
Antiobesity agent; Benzimidazole; Bioactivation; CYP3A4 time-dependent inhibition; MCH; MCHR1 antagonist; Thiophene