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

  • Bioorg Med Chem Lett. 2021 Jul 1:43:128048. doi: 10.1016/j.bmcl.2021.128048.
Mayuko Akiu  1 ,  Takashi Tsuji  2 ,  Yoshitaka Sogawa  2 ,  Koji Terayama  2 ,  Mika Yokoyama  2 ,  Jun Tanaka  2 ,  Daigo Asano  2 ,  Ken Sakurai  2 ,  Eduard Sergienko  3 ,  E Hampton Sessions  3 ,  Stephen J Gardell  4 ,  Anthony B Pinkerton  3 ,  Tsuyoshi Nakamura  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3. Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 4. Translational Research Institute, AdventHealth, Orlando, FL 32804, USA.
PMID: 33887438 DOI: 10.1016/j.bmcl.2021.128048
Abstract

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.

Keywords
CYP inhibition; LogD; NAD(+); NAMPT activators; Triazolopyridines.
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