Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5- yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine

Subhash C. Annedi, Shawn P. Maddaford, Jailall Ramnauth, Paul Renton, Taras Rybak, Sarah Silverman, Suman Rakhit, Gabriela Mladenova, Peter Dove, John S. Andrews, Dongqin Zhang, Frank Porreca

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K+ channel inhibition (IC50 = 4.7 μM) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure-activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (Fpo = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain.

Original languageEnglish (US)
Pages (from-to)94-107
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume55
DOIs
StatePublished - Sep 2012

Fingerprint

Thiophenes
Nitric Oxide Synthase Type I
Migraine Disorders
Amidines
Pain
Pharmacokinetics
Spinal Nerves
Structure-Activity Relationship
Biological Availability
Inhibitory Concentration 50
Ligation
Therapeutics
Safety
indoline
1,2,3,4-tetrahydroquinoline

Keywords

  • 1,5-Disubstituted indoline derivatives
  • Migraine
  • Nitric oxide
  • Selective neuronal nitric oxide synthase inhibitors

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5- yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine. / Annedi, Subhash C.; Maddaford, Shawn P.; Ramnauth, Jailall; Renton, Paul; Rybak, Taras; Silverman, Sarah; Rakhit, Suman; Mladenova, Gabriela; Dove, Peter; Andrews, John S.; Zhang, Dongqin; Porreca, Frank.

In: European Journal of Medicinal Chemistry, Vol. 55, 09.2012, p. 94-107.

Research output: Contribution to journalArticle

Annedi, Subhash C. ; Maddaford, Shawn P. ; Ramnauth, Jailall ; Renton, Paul ; Rybak, Taras ; Silverman, Sarah ; Rakhit, Suman ; Mladenova, Gabriela ; Dove, Peter ; Andrews, John S. ; Zhang, Dongqin ; Porreca, Frank. / Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5- yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine. In: European Journal of Medicinal Chemistry. 2012 ; Vol. 55. pp. 94-107.
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