1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors

Lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl) thiophene-2-carboximidamide as a preclinical development candidate

Jailall Ramnauth, Paul Renton, Peter Dove, Subhash C. Annedi, Joanne Speed, Sarah Silverman, Gabriela Mladenova, Shawn P. Maddaford, Salvatore Zinghini, Suman Rakhit, John Andrews, David K H Lee, Dongqin Zhang, Frank Porreca

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors, highlighted by 1 (J. Med. Chem. 2011, 54, 5562-5575). Despite showing activity in two rodent pain models, 1 suffered from low oral bioavailability (18%) and moderate hERG channel inhibition (IC 50 = 4.7 μM). To optimize the properties of 1, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters. From these studies, we identified 47 as a potent and selective nNOS inhibitor with improved oral bioavailability (60%) and no hERG channel inhibition (IC 50 > 30 μM). Furthermore, 47 was efficacious in the Chung model of neuropathic pain and has an excellent safety profile, making it a promising preclinical development candidate.

Original languageEnglish (US)
Pages (from-to)2882-2893
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number6
DOIs
StatePublished - Mar 22 2012

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Nitric Oxide Synthase Type I
Biological Availability
Neuralgia
Nervous System Diseases
Libraries
Rodentia
Safety
Pain
N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide
1,2,3,4-tetrahydroquinoline
Lead
Inhibition (Psychology)
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors : Lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl) thiophene-2-carboximidamide as a preclinical development candidate. / Ramnauth, Jailall; Renton, Paul; Dove, Peter; Annedi, Subhash C.; Speed, Joanne; Silverman, Sarah; Mladenova, Gabriela; Maddaford, Shawn P.; Zinghini, Salvatore; Rakhit, Suman; Andrews, John; Lee, David K H; Zhang, Dongqin; Porreca, Frank.

In: Journal of Medicinal Chemistry, Vol. 55, No. 6, 22.03.2012, p. 2882-2893.

Research output: Contribution to journalArticle

Ramnauth, Jailall ; Renton, Paul ; Dove, Peter ; Annedi, Subhash C. ; Speed, Joanne ; Silverman, Sarah ; Mladenova, Gabriela ; Maddaford, Shawn P. ; Zinghini, Salvatore ; Rakhit, Suman ; Andrews, John ; Lee, David K H ; Zhang, Dongqin ; Porreca, Frank. / 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors : Lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl) thiophene-2-carboximidamide as a preclinical development candidate. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 6. pp. 2882-2893.
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