أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: 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
المؤلفون: Jun Tanaka, Daigo Asano, E. Hampton Sessions, Koji Terayama, Mika Yokoyama, Mayuko Akiu, Takashi Tsuji, Ken Sakurai, Stephen J. Gardell, Yoshitaka Sogawa, Anthony B. Pinkerton, Eduard Sergienko, Tsuyoshi Nakamura
المصدر: Bioorganic & Medicinal Chemistry Letters. 43:128048
بيانات النشر: Elsevier BV, 2021.
سنة النشر: 2021
مصطلحات موضوعية: Stereochemistry, Clinical Biochemistry, Nicotinamide phosphoribosyltransferase, Pharmaceutical Science, 01 natural sciences, Biochemistry, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Cytochrome P-450 Enzyme System, Drug Discovery, Animals, Humans, Urea, Enzyme Inhibitors, Nicotinamide Phosphoribosyltransferase, Molecular Biology, Nucleotide salvage, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Activator (genetics), Organic Chemistry, Metabolism, 0104 chemical sciences, Mice, Inbred C57BL, 010404 medicinal & biomolecular chemistry, chemistry, Lipophilicity, Cytokines, Molecular Medicine, Triazolopyridine, NAD+ kinase, Lead compound
الوصف: 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.
تدمد: 0960-894X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1ab9a198b4704738f4a9ffe0b2780ffe
https://doi.org/10.1016/j.bmcl.2021.128048
حقوق: CLOSED
رقم الأكسشن: edsair.doi.dedup.....1ab9a198b4704738f4a9ffe0b2780ffe
قاعدة البيانات: OpenAIRE
الوصف
تدمد:0960894X