Carol M. Koboldt

Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors.

A series of sulfonamide-substituted 4,5-diarylthiazoles was prepared via three synthetic routes as selective COX-2 inhibitors. Recently in the synthesis of selective COX-2 inhibitors we have discovered that the sulfonamide moiety is a suitable replacement for the methylsulfonyl moiety yielding compounds with activity both in vitro and in vivo.

Diaryl indenes and benzofurans: Novel classes of potent and selective cyclooxygenase-2 inhibitors

Abstract Novel series of diaryl indenes and benzofurans have been shown to be potent and selective COX-2 inhibitors. A structure-activity relationship study suggests that the conversion of sulfones to sulfonamides affords potent, but slightly less selective COX-2 inhibitors, and that for benzofurans the 3-halo-4-methoxyphenyl sulfonamide analogs are more selective than the corresponding 4-fluorophenyl analog.

Selective cyclooxygenase inhibitors: Novel 4-spiro 1,2-diarylcyclopentenes are potent and orally active cox-2 inhibitors

Abstract Novel 4,5-diarylspiro[2.4]hept-5-enes, 6,7-diarylspiro[3.4]oct-6-enes, and 2,3-diarylspiro[4.4]non-2-enes have been synthesized and shown to be very potent inducible cyclooxygenase (COX-2) inhibitors with inhibition (IC 50 ) in the low nanomolar range and enzyme selectivity ratios as high as four orders of magnitude. The methyl sulfone spiro[2.4]hept-5-ene 1 (SC-58451) was found to be orally active (ED 50 = 0.3 mpk) in the rat adjuvant-induced arthritis model with no gastric lesions observed at 200 mpk.

Thiol and hydroxamic acid containing inhibitors of endothelin converting enzyme

Abstract A group of peptido-mimetic molecules containing either a thiol or hydroxamic acid moiety were synthesized and evaluated for in vitro inhibition of a putative endothelin converting enzyme (ECE) partially purified from rabbit lung membranes. These compounds were envisioned as analogs of the phosphoramide containing metalloprotease inhibitor phosphoramidon.

Mechanism of inhibition of novel COX-2 inhibitors.

Rome and Lands (1975) demonstrated that certain nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified by indomethacin, displayed time dependent inhibition of cyclooxygenase (COX) and that this type of time dependent inhibition is consistent with a two step model. The first step in this model represents the association of enzyme and inhibitor to form a rapidly reversible complex. The second step represents formation of an extremely tight, non-covalent complex that is only slowly reversible. With the recognition of distinct isoforms, it has also been established that COX-2 selective inhibitors are time dependent inhibitors of COX-2, but not of COX-1. This difference in mechanism of inhibition of COX-1 and COX-2 is the basis for their selectivity (Copeland et al., 1994). Time dependence of COX-2 selective inhibitors has been correlated to the presence of a side pocket present in the active site of COX-2 but not COX-1 (Gierse et al., 1996).