Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits

  • J Med Chem. 1997 Aug 1;40(16):2525-32. doi: 10.1021/jm960871c.
L J MacPherson  1 ,  E K Bayburt ,  M P Capparelli ,  B J Carroll ,  R Goldstein ,  M R Justice ,  L Zhu ,  S Hu ,  R A Melton ,  L Fryer ,  R L Goldberg ,  J R Doughty ,  S Spirito ,  V Blancuzzi ,  D Wilson ,  E M O'Byrne ,  V Ganu ,  D T Parker
Affiliations
  • 1. Research Department, Novartis Pharmaceuticals, Summit, New Jersey 07901, USA.
PMID: 9258358 DOI: 10.1021/jm960871c
Abstract

Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.

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