Scaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT).

Autor:	Palacios DS; Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States., Meredith EL; Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States., Kawanami T; Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States., Adams CM; Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States., Chen X; Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States., Darsigny V; Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States., Palermo M; Global Discovery Chemistry, Novartis Institute for Biomedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States., Baird D; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., George EL; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Guy C; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Hewett J; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Tierney L; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Thigale S; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Wang L; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States., Weihofen WA; Chemical Biology and Therapeutics, Novartis Institute for Biomedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2019 Oct 10; Vol. 10 (11), pp. 1524-1529. Date of Electronic Publication: 2019 Oct 10 (Print Publication: 2019).
DOI:	10.1021/acsmedchemlett.9b00325
Abstrakt:	Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound 27 . Competing Interests: The authors declare the following competing financial interest(s): The authors were all employees of the Novartis Institutes for Biomedical Research during the time when this work was completed. (Copyright © 2019 American Chemical Society.)
Databáze:	MEDLINE
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