The 3-arylmethylation of indoles using TMSOTf/Et3SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO2, and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. I it addition, the viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. For indoles bearing both a 6-MeSO2, and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, all unprecedented Pd(0) mediated arylorganozinc Coupling With the requisite Substituted 3-methylcarbonatomethylindole proved Successful in affording the desired 2-cyano-6-MeSO2-3-arylmethylindoles effective as selective COX-2 inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.

Two distinct synthetic schemes were applied to access heteroatom-containing alpha-chain lactams or lactams terminated as aryl acids. The latter lactams were devised using a pharmacophore for EP(4) receptor activity. gamma-Lactams were characterized for their prostanoid EP receptor affinities and EP(4) activity and found to be selective for the EP(2) and EP(4) receptors or selective for the EP(4) subtype. Benzoic acid 17 displayed enhanced in vivo exposure relative to 3.

Each of the three known human collagenases has been implicated in the degradation of the type II collagen matrix of cartilage in arthritis. RS-113,456 is a synthetic MMP inhibitor that is selective for collagenase-3 (K-I = 0.17 nM) and collagenase-2 (0.13 nM) over collagenase-1 (70 nM). RS-113,456 inhibits the IL-1 alpha-induced degradation of live bovine nasal cartilage explants in vitro, as measured by hydroxyproline loss, with an IC50 of 50 nM. To ascertain the effect of RS-113,456 on cartilage degradation in vivo, bovine nasal cartilage explants were placed in the center of a cellulose sponge, treated with a suspension of killed M. tuberculosis and implanted subcutaneously into rats. The implants were removed after 16 days, at which time the extent of collagen degradation in vehicle-treated animals was >40%. Given orally from days 1 to 15 at 5 to 30 mg/kg/day BID, RS-113,456 prevented cartilage degradation by 24 to 103%. To assess efficacy in a model of arthritis, the effect of RS-113,456 on type II collagen-induced arthritis was tested in DBA/1 mice. The maximal arthritic score was reduced in all treated groups between 23 and 70%, with p<0.05 at 20 and 40 mg/kg/day. These observations suggest that synthetic inhibitors of human collagenases may prevent cartilage degradation in human arthritis.

A new class of protein kinase C (PKC) inhibitors is described. These inhibitors were derived from the familiar bis-indolyl maleimide series of inhibitors through a structural rearrangement involving transfer of one aryl ring from the maleimide moiety to the C-2 position of the indole ring remaining attached to that moiety. The resulting compounds are among the most potent known inhibitors of PKC and also show good selectivity for PKC in relation to other kinases. The lead compound in this series possesses antitumor activity in several in vitro and in vivo models.