Synthesis and biological activity of various derivatives of a novel class of potent, selective, and orally active prostaglandin D2 receptor antagonists. 1. Bicyclo[2.2.1]heptane derivatives

J Med Chem. 2003 Jun 5;46(12):2436-45. doi: 10.1021/jm020517g.

Abstract

Novel prostaglandin D(2) (PGD(2)) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1]heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD(2) receptor in radioligand binding and cAMP formation assays with IC(50) values below 50 nM and much less antagonism of TXA(2) and PGI(2) receptors. These potent PGD(2) receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD(2) receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD(2) plays an important role in the pathogenesis of allergic diseases.

MeSH terms

  • Administration, Oral
  • Airway Obstruction / drug therapy
  • Airway Obstruction / immunology
  • Animals
  • Anti-Allergic Agents / chemical synthesis*
  • Anti-Allergic Agents / chemistry
  • Anti-Allergic Agents / pharmacology
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology
  • Capillary Permeability / drug effects
  • Conjunctiva / blood supply
  • Cyclic AMP / biosynthesis
  • Guinea Pigs
  • Hexanes / chemical synthesis*
  • Hexanes / chemistry
  • Hexanes / pharmacology
  • Humans
  • In Vitro Techniques
  • Prostaglandin D2 / metabolism*
  • Radioligand Assay
  • Receptors, Epoprostenol
  • Receptors, Immunologic*
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Thromboxane / antagonists & inhibitors
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Anti-Allergic Agents
  • Bridged Bicyclo Compounds
  • Hexanes
  • Receptors, Epoprostenol
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • Receptors, Thromboxane
  • Sulfonamides
  • Cyclic AMP
  • Prostaglandin D2
  • prostaglandin D2 receptor