Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma

J Med Chem. 2014 Feb 13;57(3):686-700. doi: 10.1021/jm401252e. Epub 2014 Jan 30.

Abstract

Selective inhibitors of neuronal nitric oxide synthase (nNOS) are regarded as valuable and powerful agents with therapeutic potential for the treatment of chronic neurodegenerative pathologies and human melanoma. Here, we describe a novel hybrid strategy that combines the pharmacokinetically promising thiophene-2-carboximidamide fragment and structural features of our previously reported potent and selective aminopyridine inhibitors. Two inhibitors, 13 and 14, show low nanomolar inhibitory potency (Ki = 5 nM for nNOS) and good isoform selectivities (nNOS over eNOS [440- and 540-fold, respectively] and over iNOS [260- and 340-fold, respectively]). The crystal structures of these nNOS-inhibitor complexes reveal a new hot spot that explains the selectivity of 14 and why converting the secondary to tertiary amine leads to enhanced selectivity. More importantly, these compounds are the first highly potent and selective nNOS inhibitory agents that exhibit excellent in vitro efficacy in melanoma cell lines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidines / chemical synthesis*
  • Amidines / chemistry
  • Amidines / pharmacology
  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cattle
  • Cell Line, Tumor / drug effects
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Melanoma / drug therapy*
  • Mice
  • Models, Molecular
  • Nitric Oxide Synthase Type I / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Rats
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • Amidines
  • Aniline Compounds
  • Antineoplastic Agents
  • Isoenzymes
  • N-(3-(2-((3-(thiophene-2-carboximidamido)benzyl)amino)ethyl)phenyl)thiophene-2-carboximidamide
  • N-(4-(2-((3-(thiophene-2-carboximidamido)benzyl)amino)ethyl)phenyl)thiophene-2-carboximidamide
  • Thiophenes
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III