Discovery and evaluation of non-basic small molecule modulators of the atypical chemokine receptor CXCR7

Bioorg Med Chem Lett. 2021 Oct 15:50:128320. doi: 10.1016/j.bmcl.2021.128320. Epub 2021 Aug 14.

Abstract

The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies.

Keywords: CXCR7; Parallel synthesis; SAR; SDF-1α.

MeSH terms

  • Animals
  • Drug Delivery Systems
  • Drug Design
  • Drug Discovery*
  • Immunologic Factors / chemical synthesis*
  • Immunologic Factors / pharmacokinetics
  • Immunologic Factors / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Structure
  • Receptors, CXCR / antagonists & inhibitors*
  • Signal Transduction
  • Structure-Activity Relationship

Substances

  • Cmkor1 protein, mouse
  • Immunologic Factors
  • Receptors, CXCR