Discovery of DS68702229 as a Potent, Orally Available NAMPT (Nicotinamide Phosphoribosyltransferase) Activator
| Autor: | Tsuyoshi Nakamura, Mika Yokoyama, Mayuko Akiu, Takashi Tsuji, Kouki Iida, Ken Sakurai, Yoshitaka Sogawa, Koji Terayama, Tomohiro Honda, Jun Tanaka, Daigo Asano, Anthony B. Pinkerton |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Nicotinamide phosphoribosyltransferase Mice Obese Type 2 diabetes Pharmacology Nicotinamide adenine dinucleotide Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound Pharmacokinetics Oral administration Drug Discovery medicine Animals Humans Urea Obesity Nicotinamide Phosphoribosyltransferase Nucleotide salvage Chemistry Activator (genetics) Body Weight General Chemistry General Medicine NAD medicine.disease Diabetes Mellitus Type 2 Anti-Obesity Agents NAD+ kinase |
| Zdroj: | Chemical and Pharmaceutical Bulletin. 69:1110-1122 |
| ISSN: | 1347-5223 0009-2363 |
| DOI: | 10.1248/cpb.c21-00700 |
| Popis: | Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the nicotinamide adenine dinucleotide (NAD+) salvage pathway. Because NAD+ plays a pivotal role in energy metabolism and boosting NAD+ has positive effects on metabolic regulation, activation of NAMPT is an attractive therapeutic approach for the treatment of various diseases, including type 2 diabetes and obesity. Herein we report the discovery of 1-(2-phenyl-1,3-benzoxazol-6-yl)-3-(pyridin-4-ylmethyl)urea 12c (DS68702229), which was identified as a potent NAMPT activator. Compound 12c activated NAMPT, increased cellular NAD+ levels, and exhibited an excellent pharmacokinetic profile in mice after oral administration. Oral administration of compound 12c to high-fat diet-induced obese mice decreased body weight. These observations indicate that compound 12c is a promising anti-obesity drug candidate. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|