Mechanistic Studies of Blood Pressure in Rats Treated With a Series of Cholesteryl Ester Transfer Protein Inhibitors

ILLUMINATE, the Phase 3 clinical trial of morbidity and mortality (M&M) with the cholesteryl ester transfer protein inhibitor (CETPi), torcetrapib (CP-529,414), was terminated in December 2006 due to an imbalance in all cause mortality. The underlying cause of the M&M remains undetermined. While torcetrapib produced dose-related increases in blood pressure in clinical trials, the mechanism of the increase in blood pressure is also undetermined. The pressor effects of torcetrapib and structurally related compounds were studied in several pathways involved in blood pressure control. Studies were conducted in rats treated with a series of structurally related molecules (CP-529,414, CP-532,623, PF-868,348, CP-746,281, CP-792,485, PF-868,343, and CE-308,958). CP-529,414, CP-532,623, CP-868,343, and CP-792,485 are potent CETP inhibitors; PF-868,348 is weakly potent and CP-746,281 and CE-308,958 are CETP-inactive. Changes in blood pressure were determined in conscious animals in conjunction with pharmacologic blockade of numerous pressor agents/pathways. Torcetrapib and CP-532,623 increased blood pressure following both chronic PO and acute IV administration. The CETP-inactive enantiomer of CP-532,623, CP-746,281 failed to raise blood pressure. PF-868,348, a structural analogue with similar to 50-fold lower CETPi activity also displayed pressor activity. Blockade of adrenergic, cholinergic, angiotensin, endothelin, NOS, Rho kinase, and thromboxane pathways failed to attenuate the pressor response. These data demonstrate that the blood pressure activity seen with torcetrapib can be dissociated from CETP inhibitor pharmacology and numerous pharmacology pathways can be discounted in the attempt to understand the molecular basis of the pressor pharmacology. Drug Dev Res 70:35-48, 2009 (C) 2009 Wiley-Liss, Inc.