Synthesis and Evaluation of Antiinflammatory Activities of a Series of Corticosteroid 17 Alpha-Esters Containing a Functional Group

J Med Chem. 1991 Aug;34(8):2468-73. doi: 10.1021/jm00112a023.

Abstract

A series of 21-desoxy-21-chlorocorticosteroids that contain a functionalized ester group at 17 alpha has been prepared and examined to separate their systemic activity from topical antiinflammatory activity. Introduction of the functionalized ester group at 17 alpha was carried out by an acid-catalyzed formation of cyclic ortho esters with 17 alpha,21-hydroxyl groups of corticosteroids and subsequent acid-catalyzed hydrolysis. As for the functional group, chloro, methoxy, acetoxy, cyano, cyclopropyl, or alkoxycarbonyl group was introduced at the terminal carbon atom of the 17 alpha-alkanoate group. The topical antiinflammatory activity and systemic activity of these compounds were examined and found to be significantly dependent on the functionalities in the 17 alpha-esters. Among these derivatives, a series of 17 alpha-(alkoxycarbonyl)alkanoates (17 alpha-OCO(CH2)nCOOR) showed an excellent separation of the systemic activity from topical activity. The effects of the number of methylene groups (n) and of the alkyl groups of the ester (R) on either topical or systemic activity of the corticosteroid derivatives were also investigated.

MeSH terms

  • Administration, Topical
  • Adrenal Cortex Hormones / chemical synthesis*
  • Adrenal Cortex Hormones / metabolism
  • Adrenal Cortex Hormones / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / therapeutic use
  • Chemical Phenomena
  • Chemistry
  • Croton Oil
  • Edema / drug therapy
  • Esterification
  • Granuloma / chemically induced
  • Granuloma / drug therapy
  • Liver / metabolism
  • Male
  • Mice
  • Molecular Structure
  • Otitis / chemically induced
  • Otitis / drug therapy
  • Rats
  • Rats, Inbred Strains
  • Receptors, Glucocorticoid / metabolism
  • Steroids
  • Structure-Activity Relationship

Substances

  • Adrenal Cortex Hormones
  • Anti-Inflammatory Agents
  • Receptors, Glucocorticoid
  • Steroids
  • Croton Oil