morphine and Peripheral-Nervous-System-Diseases

Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimerization inhibitors that although potent, suffered from high clearance and limited exposure in vivo. By conformationally restricting the amide of this progenitor series, we describe the identification of a novel series of benzimidazole-quinolinone dual iNOS/nNOS inhibitors with low clearance and sustained exposure in vivo. Compounds were triaged utilizing an LPS challenge assay coupled with mouse and rhesus pharmacokinetics and led to the identification of 4,7-imidazopyrazine 42 as the lead compound. 42 (KD7332) (J. Med. Chem. 2009, 52, 3047 - 3062) was confirmed as an iNOS dimerization inhibitor and was efficacious in the mouse formalin model of nociception and Chung model of neuropathic pain, without showing tolerance after repeat dosing. Further 42 did not affect motor coordination up to doses of 1000 mg/kg, demonstrating a wide therapeutic margin.

Topics: Administration, Oral; Analgesics; Animals; Cell Line; Drug Tolerance; Fluoroquinolones; Humans; In Vitro Techniques; Mice; Microsomes, Liver; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Pain; Pain Measurement; Peripheral Nervous System Diseases; Protein Multimerization; Pyrazines; Rotarod Performance Test; Structure-Activity Relationship

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

Topics: Analgesics; Animals; Binding Sites; Butanones; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Cerebral Ventricles; Drug Design; In Vitro Techniques; Male; Mice; Pain; Pain Measurement; Pain Threshold; PC12 Cells; Peripheral Nervous System Diseases; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship