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

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.

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

“…22, 23 Similar exterior polar amines (especially N -methyl and N,N -dimethylamines) were also effective in conferring potency and selectivity of NeurAxon’s thiophenecarboximidamides. 24, 25 …”

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

“…Compound 35 was effective in rodent neuropathic pain models following oral administration, 148 the benzazepine 36 has very high n/i selectivity (>800-fold), 145 and while 37 has low n/e selectivity, it showed no inhibition of acetylcholine-mediated relaxation in isolated human coronary arteries, lowering the probability of adverse cardiovascular events in vivo .147 Indoline 38 is a very promising candidate, which showed 66% reversal of allodynia in the Chung model, along with no hERG-related complications or off-target effects when assayed against a panel of 80 clinically relevant CNS targets. 151 Despite the in vivo successes of the NeurAxon thiophenecarboximidamides, there is no published information on the nature of their binding modes to nNOS. Another study from Northwestern 153 attempted to apply the “double-headed” strategy previously utilized for aminopyridines to thiophenecarboxamides, leading to two highly potent and selective inhibitors, 39 , and 40 ; both having >200-foldselectivity for nNOS over both other isoforms.…”

2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity

“…12,13,14 Although 3-dimensional structural information of these compounds with nNOS were not reported, our previous crystallographic experience 24 indicates that the thiophene-carboximidamide moiety should occupy the substrate binding pocket over the heme, and the tetrahydroquinoline or indole core should share the binding site with the middle aromatic ring of 3 near the C and D ring propionates. The N -methyl substituted alkylamine chains from the core should improve the selectivity and potency by interacting with residues peripheral to the active site.…”