Discovery of N-(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-6-yl) thiophene-2-carboximidamide as a Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) for the Treatment of Pain

• Published in: Journal of medicinal chemistry Vol. 54; no. 20; pp. 7408 - 7416
• Main Authors: Annedi, Subhash C, Maddaford, Shawn P, Mladenova, Gabriela, Ramnauth, Jailall, Rakhit, Suman, Andrews, John S, Lee, David K. H, Zhang, Dongqin, Porreca, Frank, Bunton, David, Christie, Lee
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.10.2011; Amer Chemical Soc
• Subjects: Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Chemistry, Medicinal; Coronary Vessels - drug effects; Coronary Vessels - physiology; Cytochrome P-450 Enzyme Inhibitors; Hot Temperature; Humans; Hyperalgesia - drug therapy; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Ligation; Neuralgia - drug therapy; Neuralgia - etiology; Nitric Oxide Synthase Type I - antagonists & inhibitors; Pain - drug therapy; Pharmacology & Pharmacy; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Science & Technology; Spinal Nerves - injuries; Stereoisomerism; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Vascular Resistance; Vasoconstriction - drug effects; SYSTEM; NO; 1-(2-TRIFLUOROMETHYLPHENYL)-IMIDAZOLE; TENSION-TYPE HEADACHE; INDOLE-DERIVATIVES; 5-HT1D RECEPTOR; MIGRAINE; MICE LACKING
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201063u

3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (−)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (−)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug–drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.