The thioester, JTT-705 41a (Figure 15), is a prodrug for the thiol-based, covalent modifier, 41b, that irreversibly inhibits CETP. While 41b effectively inhibited CETP in human plasma (IC50 = 3 mM), it was too unstable for oral dosing and necessitated the identification of a suitable prodrug moiety. The iso-butyryl ester derivative 41a (IC50 = 6 mM) was nearly equally as active in human plasma and provided the optimal combination of chemical stability and oral absorption required to move into preclinical testing.

JTT-705 (30-300 mg kg "1 day "1 p.o.) dose-dependently reduced plasma CETP activity, raised HDLc, and lowered the overall atherogenic index (i.e., the non-HDLc/HDLc ratio) after 4 weeks in animal models. In a phase II study with nearly 200 healthy subjects with mild hyperlipidemia, daily oral doses of 300, 600, and 900 mg of JTT-705 for 4 weeks were well tolerated, with 900 mg producing a maximal 34% increase in HDLc levels. The 600 mg (26%) and 300 mg (15%)

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