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Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

Authors :
Dragovich PS
Bair KW
Baumeister T
Ho YC
Liederer BM
Liu X
Liu Y
O'Brien T
Oeh J
Sampath D
Skelton N
Wang L
Wang W
Wu H
Xiao Y
Yuen PW
Zak M
Zhang L
Zheng X
Source :
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Sep 01; Vol. 23 (17), pp. 4875-85. Date of Electronic Publication: 2013 Jul 06.
Publication Year :
2013

Abstract

Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1464-3405
Volume :
23
Issue :
17
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
23899614
Full Text :
https://doi.org/10.1016/j.bmcl.2013.06.090