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  • Neuropathic pain NP is a chronic pain caused by lesion

    2022-01-14

    Neuropathic pain (NP) is a chronic pain caused by lesion or disease affecting any part of the nervous system leading to clinical conditions ranging from painful neuropathy to poststroke central pain. Anticonvulsant drugs, Gabapentin and Pregabalin, acting on αδ subunit-containing voltage-dependent calcium channels (VDCCs), and antidepressant agents such as serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine are the first-line treatment options for NP., However, their efficacies are mediocre, and also associated with several side effects including dizziness, vertigo, nausea, dry mouth and dairrhea., , , Hence, there is an unmet medical need to discover a new pharmacological class for the treatment of neuropathic pain that can also be safely combined with the current medication. We are particularly interested in condition like pain due to cancer chemotherapy-induced peripheral neuropathy (CIPN) for calcifediol receptor its growing importance in connection with the cancer chemotherapy. Fatty calcifediol receptor amide hydrolase (FAAH) is an intracellular membrane-bound enzyme that utilizes unusual catalytic triad Ser-Ser-Lys to degrade and inactivate fatty acid amide family of signaling lipids, including the endogenous cannabinoid ligands -arachidonoylethanolamine (Anandamide, AEA) and 2-arachidonoyl glycerol (2-AG). Since the discovery of FAAH as molecular target in 1996, several chemotypes have been reported and reviewed in the literature as FAAH inhibitors having reversible as well as irreversible mechanism of action., exemplifies some of the well characterized FAAH inhibitors – including those tested in early phase of clinical trials., , , , , , , , , , , , , , , , , , , , , , , , In general, pharmacological inhibition as well as genetic ablation of FAAH has been shown to be associated with increased levels of endogenous fatty acid amides (FAAs) including AEA, eliciting analgesic effects in various animal models of inflammation and chronic pain primarily via activation of endocannabinoid CB receptors. Therefore, it has been also hypothesized that a FAAH inhibitor may avoid side effects as well as abuse of cannabis and exocannabinoids. In its first wave, clinical trials with FAAH inhibitors targeted several neuropsychiatric conditions such as schizophrenia, Tourette syndrome, symptoms associated with cannabis withdrawal, and inflammatory pain due to osteoarthritis (OA). In its careful second wave, NP and major depressive disorder (MDD) are being considered as more suitable indications, evidenced by advancement of (V-158866), (ASP-8477), (SSR-411298) and (JNJ-42165279), in Phase-2 clinical trials. Interaction of Ser-241 residue of FAAH catalytic site with its inhibitors have been particularly demonstrated by co-crystal structures, initially with a substrate analog methoxy arachidonoyl fluorophosphonate (MAFP), and subsequently with non-FA based synthetic inhibitors such as, (i) OL-135 (forms reversible oxyanion intermediate), (ii) URB-597 and (iii) PF-750/3845 (ii and iii form covalently bound irreversible carbamates). We conceptualized that replacing the urea moiety in PF-3845 with an amide functional group, as depicted in newly designed analog (), might lead to a reversible inhibition, via formation of the tetrahedral oxyanion intermediate. Such an intermediate would neither have the option of permanent covalent bonding with the Ser-241 nor a hydrolysis, as the aliphatic cyclohexylamine moiety is not a good leaving group. Additionally, the newly designed scaffold would have the potential of retaining well established selectivity profile of PF-3845/04457845. Suitability of replacing the urea moiety with an amide FG was verified by docking to the co-crystal structure of PF-3845 (PDB:3LJ6) ( and ). Based on this qualitative in silico exercise, we have concluded that ()-configuration of could only be docked to the catalytic site with the desired pose as compared to its ()-enantiomer. Accordingly, a new heteroaryl amide series was invented as FAAH inhibitors broadly claiming the scaffold , and the intellectual property has been protected by PCT application. Objective of this preliminary communication is to disclose a focused set of SAR around which has also yielded two optimized leads suitable for further development.