Discovery of cis-N-(1-(4-(Methylamino)cyclohexyl)indolin-6-yl)thiophene-2-carboximidamide: A 1,6-Disubstituted Indoline Derivative as a Highly Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) without Any Cardiovascular Liabilities

• Published in: Journal of medicinal chemistry Vol. 55; no. 2; pp. 943 - 955
• Main Authors: Annedi, Subhash C, Ramnauth, Jailall, Maddaford, Shawn P, Renton, Paul, Rakhit, Suman, Mladenova, Gabriela, Dove, Peter, Silverman, Sarah, Andrews, John S, Felice, Milena D, Porreca, Frank
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.01.2012; Amer Chemical Soc
• Subjects: Analgesics - adverse effects; Analgesics - chemical synthesis; Analgesics - pharmacology; Animals; Arteries - drug effects; Arteries - physiology; Cardiovascular System - drug effects; Chemistry, Medicinal; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; HEK293 Cells; High-Throughput Screening Assays; Humans; In Vitro Techniques; Indoles - adverse effects; Indoles - chemical synthesis; Indoles - pharmacology; Life Sciences & Biomedicine; Neuralgia - drug therapy; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type III - antagonists & inhibitors; Patch-Clamp Techniques; Pharmacology & Pharmacy; Rats; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Thiophenes - adverse effects; Thiophenes - chemical synthesis; Thiophenes - pharmacology; Vascular Resistance; Vasoconstriction - drug effects; AMINATION; PROLONGATION; PREDICTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201564u

A series of 1,6-disubstituted indoline derivatives were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS) designed to mitigate the cardiovascular liabilities associated with previously reported tetrahydroquinoline-based selective neuronal NOS inhibitors due to higher lipophilicity ( J. Med. Chem. 2011, 54, 5562−5575 ). This new series produced similar potency and selectivity among the NOS isoforms and was devoid of any cardiovascular liabilities associated with QT prolongation due to hERG activity or endothelial NOS mediated vasoconstriction effect. The SAR studies led to the identification of cis-45, which was shown to reverse thermal hyperalgesia in vivo in the spinal nerve ligation model of neuropathic pain with excellent safety profile (off-target activities at 80 CNS related receptors/ion channels/transporters). The results presented in this report make cis-45 as an ideal tool for evaluating the potential role of selective nNOS inhibitors in CNS related disorders where excess NO produced by nNOS is thought to play a crucial role.