From a series of 4-amino-substituted 1,2,3,4-tetrahydroquinoline carbamates, the potent (IC50 = 0.05 mM, human plasma) CETP inhibitor torcetrapib 42 (CP-529,414; Figure 15), was identified as a lead for clinical development. In contrast to JTT-705, which modifies a key cysteine residue within the CETP protein, torcetrapib is presumably a reversible inhibitor, since it contains no obviously reactive functionalities.

Torcetrapib 42 effectively inhibited CETP-mediated transfer activity in animals and dose-dependently increased HDLc and reduced LDLc. In rabbits, oral dosing with torcetrapib inhibited CETP-mediated cholesteryl ester transfer immediately by 70-80%, produced a concomitant nearly fourfold elevation in HDLc levels, and reduced the aortic atherosclerotic lesion area by nearly 60% in the torcetrapib-treated group versus vehicle controls.

Interestingly, the LDLc lowering of torcetrapib was additive when atorvastatin was dosed simultaneously in animals. The effects observed on LDLc lowering using the torcetrapib/atorvastatin combination were greater than those observed with atorvastatin alone. These data suggest that combinations of torcetrapib and atorvastatin may have utility, and this hypothesis is being tested clinically. These initial results are the first time that additive preclinical efficacy for lowering non-HDLc has been demonstrated by combining a potent CETP inhibitor with a statin.

In clinical trials, daily oral dosing with torcetrapib at doses up to 120 mg were safe and well tolerated. A small phase II clinical proof-of-concept study compared 120 mg torcetrapib q.d. or b.i.d. for 4 weeks to placebo in subjects having low HDLc (<40mgdL_ 1) either as monotherapy or with a statin.89 One arm of this study included patients co-treated once daily with both 120 mg torcetrapib and 20 mg atorvastatin. Treatment with 120 mg torcetrapib alone inhibited plasma CETP activity by 28% given q.d. and by 65% b.i.d. After 4 weeks, 120 mg torcetrapib alone produced increases in HDLc of 46% (q.d.) and 106% (b.i.d.), compared to placebo. However, the LDLc reductions observed in this study were small and not statistically significant, even though total cholesterol levels remained unchanged. Treatment with 120 mg torcetrapib alone produced nonsignificant reductions in LDLc of 8% (q.d.) and 17% (b.i.d.). Even though these LDLc changes were not statistically significant, the LDLc reductions observed with torcetrapib alone exceeded the 7% lowering in LDLc observed clinically with JTT-705 at 900 mg_ 1 day.88 After 4 weeks, subjects co-treated daily with both 120 mg torcetrapib and 20 mg atorvastatin attained inhibition of plasma CETP activity by 38%, accompanied by a 61% increase in HDLc and a statistically significant 17% reduction in LDLc beyond that achieved with atorvastatin alone.89 Based upon these results, a torcetrapib/atorvastatin fixed combination has been selected for extensive testing in phase III trials.

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