Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a] pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition

被引：11
|
作者：
Akiu, Mayuko [1 ]
Tsuji, Takashi [1 ]
Sogawa, Yoshitaka [1 ]
Terayama, Koji [1 ]
Yokoyama, Mika [1 ]
Tanaka, Jun [1 ]
Asano, Daigo [1 ]
Sakurai, Ken [1 ]
Sergienko, Eduard [2 ]
Sessions, E. Hampton [2 ]
Gardell, Stephen J. [3 ]
Pinkerton, Anthony B. [2 ]
Nakamura, Tsuyoshi [1 ]
机构：
[1] Daiichi Sankyo Co Ltd, R&D Div, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1408710, Japan
[2] Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA
[3] AdventHealth, Translat Res Inst, Orlando, FL 32804 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 43卷
关键词：
NAMPT activators; NAD plus; Triazolopyridines; CYP inhibition; LogD; NAD BIOSYNTHESIS; MITOCHONDRIAL; METABOLISM; MONONUCLEOTIDE; SIRTUINS; RIBOSIDE; STATE;
D O I：
10.1016/j.bmcl.2021.128048
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD+ salvage pathway. Since NAD+ plays a pivotal role in many biological processes including metabolism and aging, activation of NAMPT is an attractive therapeutic target for treatment of diverse array of diseases. Herein, we report the continued optimization of novel urea-containing derivatives which were identified as potent NAMPT activators. Early optimization of HTS hits afforded compound 12, with a triazolopyridine core, as a lead compound. CYP direct inhibition (DI) was identified as an issue of concern, and was resolved through modulation of lipophilicity to culminate in 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea (21), which showed potent NAMPT activity accompanied with attenuated CYP DI towards multiple CYP isoforms.
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页数：7
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