Open AccessScaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT)
Author(s) -
Daniel S. Palacios,
Erik Meredith,
Toshio Kawanami,
Christopher M. Adams,
Xin Chen,
Véronique Darsigny,
Mark Palermo,
Daniel Baird,
Elizabeth George,
Chantale T. Guy,
Jeffrey Hewett,
Laryssa Tierney,
Sachin Thigale,
Louis Wang,
W.A. Weihofen
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00325
Subject(s) - nicotinamide phosphoribosyltransferase , adme , scaffold , chemistry , in vitro , computational biology , combinatorial chemistry , biochemistry , enzyme , nicotinamide , stereochemistry , biology , medicine , nad+ kinase , biomedical engineering
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 .