Structure-based design of COX-2 selectivity into flurbiprofen

Comparative computer modeling of the X-ray crystal structures of cyclooxyge nase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity in to the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small a lcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-I and COX-2. The design hypothesis was tested by syn thesis and biological assay of a series of flurbiprofen analogs, culminatin g in the discovery of several inhibitors having up to 78-fold selectivity f or COX-2 over COX-1. (C) 1999 Elsevier Science Ltd. All rights reserved.