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

Subhash C Annedi; Jailall Ramnauth; Shawn P Maddaford; Paul Renton; Suman Rakhit; Gabriela Mladenova; Peter Dove; Sarah Silverman; John S Andrews; Milena D Felice; Frank Porreca

doi:10.1021/jm201564u

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

J Med Chem. 2012 Jan 26;55(2):943-55. doi: 10.1021/jm201564u. Epub 2012 Jan 10.

Authors

Subhash C Annedi¹, Jailall Ramnauth, Shawn P Maddaford, Paul Renton, Suman Rakhit, Gabriela Mladenova, Peter Dove, Sarah Silverman, John S Andrews, Milena D Felice, Frank Porreca

Affiliation

¹ NeurAxon Inc. , 2395 Speakman Drive, Suite 1001, Mississauga, Ontario L5K 1B3, Canada.

PMID: 22175766
DOI: 10.1021/jm201564u

Abstract

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.

MeSH terms

Analgesics / adverse effects
Analgesics / chemical synthesis*
Analgesics / pharmacology
Animals
Arteries / drug effects
Arteries / physiology
Cardiovascular System / drug effects*
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
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
Rats
Stereoisomerism
Structure-Activity Relationship
Thiophenes / adverse effects
Thiophenes / chemical synthesis*
Thiophenes / pharmacology
Vascular Resistance
Vasoconstriction / drug effects

Substances

Analgesics
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Indoles
KCNH2 protein, human
N-(1-(4-(methylamino)cyclohexyl)indolin-6-yl)thiophene-2-carboximidamide
Thiophenes
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III