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Robl, J A; Sulsky, R; Sun, C Q; Simpkins, L M; Wang, T; Dickson, Jr, J K; Chen, Y; Magnin, D R; Taunk, P; Slusarchyk, W A; Biller, S A; Lan, S J; Connolly, F; Kunselman, L K; Sabrah, T; Jamil, H; Gordon, D; Harrity, T W; Wetterau, J R
Journal of medicinal chemistry, 03/2001, Letnik: 44, Številka: 6Journal Article
A series of benzimidazole-based analogues of the potent MTP inhibitor BMS-201038 were discovered. Incorporation of an unsubstituted benzimidazole moiety in place of a piperidine group afforded potent inhibitors of MTP in vitro which were weakly active in vivo. Appropriate substitution on the benzimidazole ring, especially with small alkyl groups, led to dramatic increases in potency, both in a cellular assay of apoB secretion and especially in animal models of cholesterol lowering. The most potent in this series, 3g (BMS-212122), was significantly more potent than BMS-201038 in reducing plasma lipids (cholesterol, VLDL/LDL, TG) in both hamsters and cynomolgus monkeys.
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