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.

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.

• Authors: Marvin J Meyers, Scott A Long, Matthew J Pelc, Jane L Wang, Scott J Bowen, Barbara A Schweitzer, Mark V Wilcox, Joseph McDonald, Sarah E Smith, Susan Foltin, Jeanne Rumsey, Young-Sun Yang, Mark C Walker, Satwik Kamtekar, David Beidler, Atli Thorarensen
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 21 Pg. 6545-53 (Nov 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21924613 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• Aza Compounds
• Enzyme Inhibitors
• PF-04862853
• Spiro Compounds
• Amidohydrolases
• fatty-acid amide hydrolase

Topics

• Administration, Oral
• Amidohydrolases (antagonists & inhibitors)
• Analgesics (administration & dosage, chemistry, pharmacology, therapeutic use)
• Animals
• Aza Compounds (administration & dosage, chemistry, pharmacology, therapeutic use)
• Biological Availability
• Chromatography, High Pressure Liquid
• Drug Discovery
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (administration & dosage, chemistry, pharmacology, therapeutic use)
• Pain (drug therapy)
• Rats
• Spiro Compounds (administration & dosage, chemistry, pharmacology, therapeutic use)