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Related Experiment Video

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Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
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1-BENZYLSPIRO[PIPERIDINE-4,1'-PYRIDO[3,4-b]indole] 'co-potentiators' for minimal function CFTR mutants.

Jung-Ho Son1, Puay-Wah Phuan2, Jie S Zhu1

  • 1Department of Chemistry, University of California, Davis, CA, 95616, USA.

European Journal of Medicinal Chemistry
|October 23, 2020
PubMed
Summary

Researchers developed novel spiro [piperidine-4,1-pyrido [3,4-b]indole] compounds to enhance cystic fibrosis transmembrane conductance regulator (CFTR) function. The most potent analog significantly improved N1303K-CFTR activation, offering a promising therapeutic avenue.

Keywords:
CFTRCystic fibrosisModulatorN1303K-CFTRPotentiatorc.3700A>G

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Biochemistry

Background:

  • Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators are crucial for treating cystic fibrosis.
  • Existing potentiators show limited efficacy with certain CFTR mutations.
  • A spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators was previously identified.

Purpose of the Study:

  • To improve the potency of spiro [piperidine-4,1-pyrido [3,4-b]indole] co-potentiators.
  • To identify structure-activity relationships for enhanced CFTR potentiation.
  • To develop novel therapeutic agents for minimal function CFTR mutants.

Main Methods:

  • Synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indole] analogs.
  • Structure-activity relationship (SAR) studies.
  • Potency assessment of analogs for N1303K-CFTR activation.

Main Results:

  • Efficient two or three-step synthesis protocols were established.
  • Analog 2i, featuring 6'-methoxyindole and 2,4,5-trifluorobenzyl groups, demonstrated superior potency.
  • Analog 2i achieved an EC50 of approximately 600 nM for N1303K-CFTR activation, a 17-fold improvement.

Conclusions:

  • Novel spiro [piperidine-4,1-pyrido [3,4-b]indole] analogs exhibit significantly enhanced CFTR potentiator activity.
  • Analog 2i represents a promising lead compound for treating specific cystic fibrosis mutations.
  • These findings advance the development of targeted CFTR modulators.