Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain |
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Authors: | Meyers Marvin J Long Scott A Pelc Matthew J Wang Jane L Bowen Scott J Schweitzer Barbara A Wilcox Mark V McDonald Joseph Smith Sarah E Foltin Susan Rumsey Jeanne Yang Young-Sun Walker Mark C Kamtekar Satwik Beidler David Thorarensen Atli |
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Affiliation: | Pfizer Global Research & Development, St. Louis Laboratories, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States. mmeyers8@slu.edu |
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Abstract: | Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate. |
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Keywords: | FAAH, fatty acid amide hydrolase AEA, anandamide ABPP, activity-based protein profiling CFA, complete Freund’s adjuvant MED, minimum efficacious dose SAR, structure-activity relationship CNS, central nervous system PK, pharmacokinetic |
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