Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

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The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.

A series of y-and &lactones including several aldonolactones were reacted with (chloromethy1)aluminum 2-(2-propenyl)anilide to produce the Corresponding hydroxy amides. Protection using [ (trimethylsilyl)ethoxy]methyl chloride, (2-methoxyethoxy)methyl chloride, methoxymethyl chloride, tert-butyldimethylsilyl chloride, or tert-butyldiphenylsilyl chloride followed by ozonolysis gave the protected N-(y-or 6-hydroxyacy1)indole derivatives. Mild saponification gave indole and the acetal-or silyl-protected hydroxy acid.

Inflammatory mediator release is one of the body's responses to tissue injury and inflammation. These mediators, such as interleukin-1 beta (I1-1 beta), tumor necrosis factor (TNF-alpha), and products of arachidonic acid metabolism, are themselves proinflammatory. Purified human monocytes stimulated in vitro with E. coli-derived lipopolysaccharide (LPS) will release these key cytokines along with various other eicosanoid mediators. Monocytes incubated with LPS and the prostaglandin E-1 analog, misoprostol, released significantly lower levels of cytokines compared to monocytes incubated with LPS alone. Eicosanoid release was also affected by misoprostol. SC-46275, a more potent mucosal protective PGE1 analog, also altered the release of cytokines and eicosanoids from human monocytes. However SC-46275 inhibited I1-1 beta release with an IC50 value of 9 microM compared to 75 microM for misoprostol. SC-46275 and misoprostol both inhibited TNF-alpha release. These data suggest there is a potential immunomodulatory role for prostaglandin analogs in the therapeutic treatment of inflammatory diseases such as ulcerative colitis, Crohn's disease, and autoimmune inflammatory diseases of the central nervous system.

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