SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).

Autor: Curtin ML; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: mike.curtin@abbvie.com., Heyman HR; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Clark RF; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Sorensen BK; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Doherty GA; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Hansen TM; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Frey RR; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Sarris KA; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Aguirre AL; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Shrestha A; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Tu N; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Woller K; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Pliushchev MA; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Sweis RF; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Cheng M; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Wilsbacher JL; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Kovar PJ; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Guo J; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Cheng D; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Longenecker KL; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Raich D; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Korepanova AV; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Soni NB; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Algire MA; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Richardson PL; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Marin VL; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Badagnani I; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Vasudevan A; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Buchanan FG; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Maag D; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Chiang GG; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Tse C; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States., Michaelides MR; AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Aug 01; Vol. 27 (15), pp. 3317-3325. Date of Electronic Publication: 2017 Jun 14.
DOI: 10.1016/j.bmcl.2017.06.018
Abstrakt: Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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