The synthesis of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as potent CRTh2 antagonists

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5344-5348. doi: 10.1016/j.bmcl.2017.07.064. Epub 2017 Jul 25.

Abstract

New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.

Keywords: 1-Oxo-1,2-dihydroisoquinoline; Asthma; CRTh(2) antagonists; Intramolecular cyclization; Isoquinolinone; Respiratory diseases.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Molecular Structure
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Isoquinolines
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • prostaglandin D2 receptor