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

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3317-3325. doi: 10.1016/j.bmcl.2017.06.018.

Michael L Curtin ¹, H Robin Heyman ², Richard F Clark ², Bryan K Sorensen ², George A Doherty ², T Matthew Hansen ², Robin R Frey ², Kathy A Sarris ², Ana L Aguirre ², Anurupa Shrestha ², Noah Tu ², Kevin Woller ², Marina A Pliushchev ², Ramzi F Sweis ², Min Cheng ², Julie L Wilsbacher ², Peter J Kovar ², Jun Guo ², Dong Cheng ², Kenton L Longenecker ², Diana Raich ², Alla V Korepanova ², Nirupama B Soni ², Mikkel A Algire ², Paul L Richardson ², Violeta L Marin ², Ilaria Badagnani ², Anil Vasudevan ², F Greg Buchanan ², David Maag ², Gary G Chiang ², Chris Tse ², Michael R Michaelides ²

Affiliations

1 AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: mike.curtin@abbvie.com.
2 AbbVie Inc, 1 North Waukegan Rd., North Chicago, IL 60064, United States.

PMID: 28610984 DOI: 10.1016/j.bmcl.2017.06.018

Abstract

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.

Keywords

Antitumor activity; Cancer; Isoindoline ureas; NAMPT inhibitors.

Name
Email *

	Sorry, but the email address you supplied was invalid.