Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2014 Jan 1;24(1):337-43. doi: 10.1016/j.bmcl.2013.11.006. Epub 2013 Nov 14.

Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.

Author information

1
Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA. Electronic address: xzheng@formatherapeutics.com.
2
Forma Therapeutics, Inc., 500 Arsenal Street, Watertown, MA 02472, USA.
3
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
4
Pharmaron Beijing, Co. Ltd, 6 Tai He Road, BDA, Beijing 100176, PR China.

Abstract

A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.

KEYWORDS:

Nampt; Nicotinamide phosphoribosyltransferase; X-ray crystal structure; cyanoguanidine

PMID:
24279990
DOI:
10.1016/j.bmcl.2013.11.006
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center