Discovery and optimization of indole pyrrolothiazole paf antagonists

✍ Scribed by James H. Holms; Steven K. Davidsen; George S. Sheppard; George M. Carrera Jr.; Nichael L. Curtin; H.Robin Heyman; Daisy Pireh; Douglas H. Steinman; Daniel H. Albert; Richard G. Conway; Gongjin Luo; Terrance J. Magoc; Paul Tapang; David A. Rhein; James B. Summers

• Book ID: 103983184
• Publisher: Elsevier Science
• Year: 1995
• Tongue: English
• Weight: 303 KB
• Volume: 5
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/0960-894x(95)00509-r

✦ Synopsis

3-(3-Pyridinyl)-7-(indol-3-ylcarbonyl)-lH-3H-pyrrolo[l,2-c]thiazoles represent a new class of platelet activating factor antagonists. This series was discovered by combining the indole portion of a previous thiazolidine series with the known 3-pyridi~yl-pyrrolothiazole pharmacophore. Optiraization of the indole substituents resulted in the identification of gi as one of the most potent PAF antagonists yet described.

Platelet Activating Factor (PAP') is an endogenous phospholipid inflammatory mediator which exhibits a wide spectrum of biological activities via stimulation of specific G-protein coupled receptors found on a variety of cell types. 1 The biological effects induced by PAF include bronchoconstriction, vascular permeability, hypotension, and platelet degranulation. It has been implicated as an important mediator in inflammatory diseases including asthma, allergic rhinitis, septic shock, pancreatitis, and ischemia reperfusion injury. 2