Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model

[Display omitted] •Novel scaffold as FAAH inhibitor with reversible mechanism of action.•Proof of MoA by recovery of active enzyme upon preincubation with inhibitor.•Synthesis via diastereomeric resolution of novel chiral dissymmetric intermediate.•Drug-like DMPK properties of Opt. Leads (−)-12l-m s...

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Published in:Bioorganic & medicinal chemistry letters 2019-01, Vol.29 (2), p.238-243
Main Authors: Bhuniya, Debnath, Kharul, Rajendra K., Hajare, Atul, Shaikh, Nadim, Bhosale, Sandeep, Balwe, Sandip, Begum, Fouzia, De, Siddhartha, Athavankar, Sonalee, Joshi, Dhananjay, Madgula, Vamsi, Joshi, Kaushal, Raje, Amol A., Meru, Ashwinkumar V., Magdum, Amol, Mookhtiar, Kasim A., Barbhaiya, Rashmi
Format: Article
Language:English
Subjects:
Chemotherapy-induced peripheral neuropathy
Diastereomeric resolution
Fatty acid amide hydrolase (FAAH) inhibitors
Reversible mechanism of action
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Summary:[Display omitted] •Novel scaffold as FAAH inhibitor with reversible mechanism of action.•Proof of MoA by recovery of active enzyme upon preincubation with inhibitor.•Synthesis via diastereomeric resolution of novel chiral dissymmetric intermediate.•Drug-like DMPK properties of Opt. Leads (−)-12l-m suitable for preclinical development.•Antihyperalgesic effects, in rat CIPN model at 3–30 mg/kg po dose. Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (−)-12a, (−)-12i, (−)-12l–m. The required (−)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (−)-12l and (−)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3–30 mg/kg po for 7 days. The effects at 30 mg/kg are comparable to that of PF-04457845 (10 mg/kg) and Tramadol (40 mg/kg).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.11.048