2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors

Dhananjayan Vasu, Huiying Li, Christine D. Hardy, Thomas L. Poulos*, Richard B. Silverman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS) based on the 2-aminopyridine scaffold with a shortened amino sidechain is reported. A rapid and simple protocol was developed to access these inhibitors in excellent yields. Neuronal nitric oxide synthase (nNOS) is a novel therapeutic target for the treatment of various neurological disorders. The major challenges in designing nNOS inhibitors in humans focus on potency, selectivity over other isoforms of nitric oxide synthases (NOSs), and blood–brain barrier permeability. In this context, we discovered a promising inhibitor, 6-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-methylpyridin-2-amine dihydrochloride, that exhibits excellent potency for rat (Ki = 46 nM) and human nNOS (Ki = 48 nM), respectively, with 388-fold human eNOS and 135-fold human iNOS selectivity. It also displayed excellent permeability (Pe = 17.3 × 10-6 cm s-1) through a parallel artificial membrane permeability assay, a model for blood–brain permeability. We found that increasing lipophilicity by incorporation of fluorine atoms on the backbone of the inhibitors significantly increased potential blood–brain barrier permeability. In addition to measuring potency, isoform selectivity, and permeability of NOS inhibitors, we also explored structure–activity relationships via structures of key inhibitors complexed to various isoforms of nitric oxide synthases.

Original languageEnglish (US)
Article number116878
JournalBioorganic and Medicinal Chemistry
Volume69
DOIs
StatePublished - Sep 1 2022

Keywords

  • 2-Aminopyridines
  • Blood-brain barrier
  • Fluorine
  • Molecular rigidity
  • Neurodegeneration
  • Nitric oxide
  • Nitric oxide synthases
  • PAMPA-BBB penetration

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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