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%)

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook

Post a comment