2D Quantitative structure–activity relationship studies on a series of cholesteryl ester transfer protein inhibitors Marcelo S. Castilho, a, * Rafael V. C. Guido b and Adriano D. Andricopulo b a Laborato ´ rio de Bioinforma ´ tica e Modelagem Molecular, Faculdade de Farma ´ cia, Universidade Federal da Bahia, Campus Universita ´ rio de Ondina, 40170-290 Salvador, BA, Brazil b Laborato ´ rio de Quı ´mica Medicinal e Computacional, Centro de Biotecnologia Molecular Estrutural, Instituto de Fı ´sica de Sa ˜o Carlos, Universidade de Sa ˜o Paulo, Av. Trabalhador Sa ˜o-Carlense 400, 13560-970 Sa ˜o Carlos, SP, Brazil Received 11 May 2007; revised 6 June 2007; accepted 8 June 2007 Available online 13 June 2007 Abstract—Coronary heart disease (CHD) is one of the major causes of human death. The most successful therapeutic approach available is based on the reduction of low density-lipoprotein cholesterol (LDL-C). However, it is believed that the next paradigm in CHD treatment will rely on increased HDL-C levels. One of the most promising strategies for this goal is the inhibition of cholesteryl ester transfer protein (CETP). In the present work, robust classical 2D QSAR (r 2 = 0.76, q 2 = 0.72) and hologram QSAR (r 2 = 0.88, q 2 = 0.70) models were developed for a series of 85 CETP inhibitors (N-N-disubstituted trifluoro-3-amino-2-propanol derivatives). These models are complementary in nature and highlight important structural features for the design of novel CETP inhibitors with improved potency. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction Although coronary heart disease (CHD) mortality has been diminishing in Western Europe and North Amer- ica for the past decades, it remains one of the major causes of human death. 1,2 In the past two decades, the most successful therapeutic approach for the treatment of this disease is based on the reduction of low den- sity-lipoprotein cholesterol (LDL-C) levels. 3 Accord- ingly, statins have become the gold standard treatment for patients with, or at risk for, CHD. 4 However, despite the great benefits of statins, the outcome of many trea- ted patients is still unsatisfactory, requiring immediate attention. 5 Furthermore, epidemiologic studies have identified that low levels of high density-lipoprotein cho- lesterol (HDL-C) are a higher risk for CHD than LDL- C, total cholesterol or plasma triglycerides (TG). 6 Therefore, it is believed that the next frontier in CHD treatment should rely on increased HDL-C levels. 7 Nevertheless, the available drugs for CHD management have poor effects on HDL-C levels (Fig. 1): niacin has by far the best profile, raising the level of HDL-C by as much as 30%, however, its cutaneous flushing side-effect limits the patient compliance 8 ; Fibrates (e.g., gemfibro- zil, fenofibrate) increase HDL-C by 15–25% in patients with hypertriglyceridemia, but have little effect (<10%) on other patients; statins (e.g., atorvastatin, simvastatin) produce only modest effect on HDL-C levels (approxi- mately 5%). 9–11 This fact highlights the importance of probing more effective strategies to increase HCL-C lev- els. 5,6,8 This goal can be achieved through the inhibition of cholesteryl ester transfer protein (CETP). However, recent clinical trials moderated the perspectives on CETP inhibition as a good target for CHD patients. Although torcetrapib, an irreversible inhibitor of CETP, in association with atorvastatin substantially increased HDL-C and decreased LDL-C when compared with atorvastatin monotherapy, no significant reduction in the progression of coronary atherosclerosis was ob- served. 12 Although the use of torcetrapib was associated with increased blood pressure, there are a number of CETP inhibitors that do not show similar effects. There- fore, there is an increasing interest in the study of new classes of CETP inhibitors aimed at developing thera- pies to raise HDL cholesterol levels. 12 0968-0896/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2007.06.021 Keywords: QSAR; Coronary heart disease; Trifluoro-3-amino-2-pro- panol derivatives; CETP; Inhibitors. * Corresponding author. Tel.: +55 71 3332 1580; fax: +55 71 3235 9350; e-mail: castilho@ufba.br Bioorganic & Medicinal Chemistry 15 (2007) 6242–6252