Identification of potent, noncovalent fatty acid amide hydrolase (FAAH) inhibitors

Darin J Gustin; Zhihua Ma; Xiaoshan Min; Yihong Li; Christine Hedberg; Cris Guimaraes; Amy C Porter; Michelle Lindstrom; Dianna Lester-Zeiner; Guifen Xu; Timothy J Carlson; Shouhua Xiao; Cesar Meleza; Richard Connors; Zhulun Wang; Frank Kayser

doi:10.1016/j.bmcl.2011.02.052

Identification of potent, noncovalent fatty acid amide hydrolase (FAAH) inhibitors

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2492-6. doi: 10.1016/j.bmcl.2011.02.052. Epub 2011 Feb 17.

Authors

Darin J Gustin¹, Zhihua Ma, Xiaoshan Min, Yihong Li, Christine Hedberg, Cris Guimaraes, Amy C Porter, Michelle Lindstrom, Dianna Lester-Zeiner, Guifen Xu, Timothy J Carlson, Shouhua Xiao, Cesar Meleza, Richard Connors, Zhulun Wang, Frank Kayser

Affiliation

¹ Department of Chemistry, Amgen Inc., South San Francisco, 1120 Veterans Blvd., South San Francisco, CA 94080, USA. dgustin@amgen.com

PMID: 21392988
DOI: 10.1016/j.bmcl.2011.02.052

Abstract

Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these compounds was determined through a combination of SAR and co-crystallography with rat FAAH.

MeSH terms

Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / metabolism
Animals
Binding Sites
Computer Simulation
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
Humans
Lactams / chemical synthesis
Lactams / chemistry
Lactams / pharmacokinetics
Rats
Spiro Compounds / chemistry
Structure-Activity Relationship
Urea / chemical synthesis
Urea / chemistry
Urea / pharmacokinetics

Substances

Enzyme Inhibitors
Lactams
Spiro Compounds
Urea
Amidohydrolases
fatty-acid amide hydrolase