1-BENZYLSPIRO[PIPERIDINE-4,1'-PYRIDO[3,4-b]indole] 'co-potentiators' for minimal function CFTR mutants

Eur J Med Chem. 2021 Jan 1:209:112888. doi: 10.1016/j.ejmech.2020.112888. Epub 2020 Oct 8.

Abstract

We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.

Keywords: CFTR; Cystic fibrosis; Modulator; N1303K-CFTR; Potentiator; c.3700A>G.

MeSH terms

  • Aminophenols / pharmacology
  • Animals
  • Cell Line
  • Chloride Channel Agonists / chemical synthesis
  • Chloride Channel Agonists / chemistry*
  • Chloride Channel Agonists / pharmacology*
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / agonists*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Models, Molecular
  • Mutation
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Quinolones / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Aminophenols
  • Chloride Channel Agonists
  • Indoles
  • Piperidines
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor