Discovery and Characterization of a Highly Selective FAAH Inhibitor that Reduces Inflammatory Pain

被引：370

作者：

Ahn, Kay ^{[1
]}

Johnson, Douglas S. ^{[1
]}

Mileni, Mauro ^{[2
]}

Beidler, David ^{[3
]}

Long, Jonathan Z. ^{[4
,5
]}

McKinney, Michele K. ^{[4
,5
]}

Weerapana, Eranthie ^{[4
,5
]}

Sadagopan, Nalini ^{[6
]}

Liimatta, Marya ^{[7
]}

Smith, Sarah E. ^{[3
]}

Lazerwith, Scott ^{[6
]}

Stiff, Cory ^{[1
]}

Kamtekar, Satwik ^{[3
]}

Bhattacharya, Keshab ^{[3
]}

Zhang, Yanhua ^{[1
]}

Swaney, Stephen ^{[6
]}

Van Becelaere, Keri ^{[6
]}

Stevens, Raymond C. ^{[2
]}

Cravatt, Benjamin F. ^{[4
,5
]}

机构：

[1] Pfizer Inc, Global Res & Dev, Groton, CT 06340 USA

[2] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA

[3] Pfizer Global Res & Dev, Chesterfield, MO 63017 USA

[4] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[5] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA

[6] Pfizer Global Res & Dev, Ann Arbor, MI 48105 USA

[7] Pfizer Global Res & Dev, Cambridge, MA 02139 USA

来源：

CHEMISTRY & BIOLOGY | 2009年 / 16卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ACID AMIDE HYDROLASE; MOLECULAR CHARACTERIZATION; ENDOCANNABINOID SYSTEM; ANANDAMIDE HYDROLYSIS; REVERSIBLE INHIBITORS; MULTIPLE MECHANISMS; CANNABINOID SYSTEM; SERINE HYDROLASES; ENZYME; MICE;

D O I：

10.1016/j.chembiol.2009.02.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

引用

页码：411 / 420

页数：10

共 49 条

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