Identification of a novel, non-tetrahydroquinoline variant of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, with improved aqueous solubility

References

• Allan G, Davis J, Dickins M, et al. (2008). Pre-clinical pharmacokinetics of UK-453,061, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) and use of in silico physiologically based prediction tools to predict the oral pharmacokinetics of UK-453,061 in man. Xenobiotica 38:620–40
   PubMed Web of Science ®Google Scholar
• Barter PJ, Brewer HB Jr, Chapman MJ, et al. (2003). Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 23:160–7
   PubMed Web of Science ®Google Scholar
• Barter PJ, Caulfield M, Eriksson M, et al. (2007). Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357:2109–22
   PubMed Web of Science ®Google Scholar
• Cannon CP, Shah S, Dansky HM, et al. (2010). Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 363:2406–15
   PubMed Web of Science ®Google Scholar
• Cao G, Beyer TP, Zhang Y, et al. (2011). Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure. J Lipid Res 52:2169–75
   PubMed Web of Science ®Google Scholar
• Chuang VT, Maruyama T, Otagiri M. (2009). Updates on contemporary protein binding techniques. Drug Metab Pharmacokinet 24:358–64
   PubMed Web of Science ®Google Scholar
• Clark RW, Ruggeri RB, Cunnigham D, Bamberger MJ. (2006). Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action. J Lipid Res 47:537–52
   PubMed Web of Science ®Google Scholar
• Clark RW, Sutfin TA, Ruggeri RB, et al. (2004). Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 24:490–7
   PubMed Web of Science ®Google Scholar
• Clerc RG, Stauffer A, Weibel F, et al. (2010). Mechanisms underlying off-targets effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens 28:1676–86
   PubMed Web of Science ®Google Scholar
• Chiou WL, Barve A. (1998). Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharm Res 15:1792–5
   PubMed Web of Science ®Google Scholar
• Dalvie D, Chen W, Zhang C, et al. (2008). Pharmacokinetics, metabolism, and excretion of torcetrapib, a cholesteryl ester transfer protein inhibitor, in humans. Drug Metab Dispos 36:2185–98
   PubMed Web of Science ®Google Scholar
• Davidson MH, McKenney JM, Shear CL, Revkin JH. (2006). Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels. J Am Coll Cardiol 48:1774–81
   PubMed Web of Science ®Google Scholar
• Derks M, Fowler S, Kuhlmann O. (2009). A single-center, open-label, one-sequence study of dalcetrapib coadministered with ketoconazole, and an in vitro study of the S-methyl metabolite of dalcetrapib. Clin Ther 31:586–99
   PubMed Web of Science ®Google Scholar
• Fisher MB, Henne KR, Boer J. (2006). The complexities inherent in attempts to decrease drug clearance by blocking sites of CYP-mediated metabolism. Curr Opin Drug Discov Dev 9:101–9
   PubMed Web of Science ®Google Scholar
• Forrest MJ, Bloomfield D, Briscoe RJ, et al. (2008). Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 154:1465–73
   PubMed Web of Science ®Google Scholar
• Hagmann WK. (2008). The many roles for fluorine in medicinal chemistry. J Med Chem 51:4359–69
   PubMed Web of Science ®Google Scholar
• Hosea NA, Collard WT, Cole S, et al. (2009). Prediction of human pharmacokinetics from preclinical information: comparative accuracy of quantitative prediction approaches. J Clin Pharmacol 49:513–33
   PubMed Web of Science ®Google Scholar
• Hu X, Dietz JD, Xia C, et al. (2009). Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesterol ester transfer protein inhibition. Endocrinology 150:2211–19
   PubMed Web of Science ®Google Scholar
• Inazu A, Brown ML, Hesler CB, et al. (1990). Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med 323:1234–8
   PubMed Web of Science ®Google Scholar
• Johns DG, Duffy J, Fisher T, et al. (2012). On- and off-target pharmacology of torcetrapib: current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors. Drugs 72:491–507
   PubMedGoogle Scholar
• Krishna R, Anderson MS, Bergman AJ, et al. (2007). Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 370:1907–14
   PubMed Web of Science ®Google Scholar
• Krishna R, Bergman AJ, Green M, et al. (2011). Model-based development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor. AAPS J 13:179–90
   PubMed Web of Science ®Google Scholar
• Krishna R, Bergman AJ, Jin B, et al. (2008). Multiple-dose pharmacodynamics and pharmacokinetics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Clin Pharmacol Ther 84:679–83
   PubMed Web of Science ®Google Scholar
• Kuhlmann O, Heinig K. (2011). Dalcetrapib pharmacokinetics and metabolism in the cynomolgus monkey. Xenobiotica 41:430–6
   PubMed Web of Science ®Google Scholar
• Kumar S, Tan EY, Hartmann G, et al. (2010). Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans. Drug Metab Dispos 38:474–83
   PubMed Web of Science ®Google Scholar
• Lee C, Gallo J, Arikpo W, Bobin V. (2007). Comparison of extraction techniques for spray dried dispersion tablet formulations. J Pharm Biomed Anal 45:565–71
   PubMedGoogle Scholar
• Lim GB. (2013). Lipids. Dalcetrapib raises HDL-cholesterol level, but does not reduce cardiac risk. Nat Rev Cardiol 10:5
   PubMedGoogle Scholar
• Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26
   PubMed Web of Science ®Google Scholar
• Lombardo F, Waters NJ, Argikar UA, et al. (2013). Comprehensive assessment of human pharmacokinetic prediction based on in vivo animal pharmacokinetic data, part 2: clearance. J Clin Pharmacol 53:178–91
   PubMed Web of Science ®Google Scholar
• Mantlo NB, Escribano A. (2013). Update on the discovery and development of cholesteryl ester transfer protein inhibitors for reducing residual cardiovascular risk. J Med Chem. [Epub ahead of print]. DOI: 10.1021/jm400574e
   PubMedGoogle Scholar
• Mistryyukov EA, Aronova NI. (1967). Basicity of amine of the piperidine series and dependence of the basicity upon steric and polar factors. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya 4:789–93
   Google Scholar
• Mullangi R, Ahlawat P, Trivedi RK, Srinivas NR. (2009). Use of bile correction factors for allometric prediction of human pharmacokinetic parameters of torcetrapib, a facile cholesteryl ester transfer protein inhibitor. Eur J Drug Metab Pharmacokinet 34:57–63
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Brewer HB, Kastelein JJ, et al. (2011). Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with stains on HDL and LDL cholesterol. J Am Med Ass 306:2099–109
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Tuzcu EM, Brennan DM, et al. (2008). Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 118:2506–14
   PubMed Web of Science ®Google Scholar
• Niesor EJ, Magg C, Ogawa N, et al. (2010). Modulating cholesteryl ester transfer protein activity maintains efficient pre-b-HDL formation and increases reverse cholesterol transport. J Lipid Res 51:3443–54
   PubMed Web of Science ®Google Scholar
• Obach RS. (1999). Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350–9
   PubMed Web of Science ®Google Scholar
• Obach RS. (2000). Inhibition of human cytochrome P450 enzymes by constituents of St. John’s wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther 294:88–95
   PubMed Web of Science ®Google Scholar
• Pacifici GM, Viani A. (1992). Methods of determining plasma and tissue binding of drugs. Clin Pharmacokinet 23:449–68
   PubMed Web of Science ®Google Scholar
• Park BK, Kitteringham NR, O’Neill PM. (2001). Metabolism of fluorine-containing drugs. Annu Rev Pharmacol Toxicol 41:443–70
   PubMed Web of Science ®Google Scholar
• Perlman ME, Murdande SB, Gumkowski MJ, et al. (2008). Development of a self-emulsifying formulation that reduces the food effect for torcetrapib. Int J Pharm 351:15–22
   PubMed Web of Science ®Google Scholar
• Prakash C, Chen W, Rossulek M, et al. (2008). Metabolism, pharmacokinetics, and excretion of a cholesteryl ester transfer protein inhibitor, torcetrapib, in rats, monkeys, and mice: characterization of unusual and novel metabolites by high-resolution liquid chromatography-tandem mass spectrometry and 1H nuclear magnetic resonance. Drug Metab Dispos 36:2064–79
   PubMed Web of Science ®Google Scholar
• Ranalletta M, Bierilo KK, Chen Y, et al. (2010). Biochemical characterization of cholesteryl ester transfer protein inhibitors. J Lipid Res 51:2739–52
   PubMed Web of Science ®Google Scholar
• Rhainds D, Arsenault BJ, Brodeur MR, Tardif JC. (2012). An update on the clinical development of dalcetrapib (RO4607381), a cholesteryl ester transfer protein modulator that increases HDL cholesterol levels. Future Cardiol 8:513–31
   PubMedGoogle Scholar
• Robinson JG. (2010). Dalcetrapib: a review of Phase II data. Expert Opin Investig Drugs 19:795–805
   PubMed Web of Science ®Google Scholar
• Schuhmacher J, Buhner K, Witt-Laido A. (2000). Determination of the free fraction and relative free fraction of drugs strongly bound to plasma proteins. J Pharm Sci 89:1008–21
   PubMed Web of Science ®Google Scholar
• Schuhmacher J, Kohlsdorfer C, Buhner K, et al. (2004). High-throughput determination of the free fraction of drugs strongly bound to plasma proteins. J Pharm Sci 93:816–30
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Olsson AG, Abt M, et al. (2012). Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 367:2089–99
   PubMed Web of Science ®Google Scholar
• Sofat R, Hingorani AD, Smeeth L, et al. (2010). Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation 121:52–62
   PubMed Web of Science ®Google Scholar
• Stroes ES, Kastelein JJ, Bénardeau A, et al. (2009). Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin angiotensin-aldosterone system in rats. Br J Pharmacol 158:1763–70
   PubMed Web of Science ®Google Scholar
• Takenaka H, Kawashima Y, Lin SY. (1981). Polymorphism of spray-dried microencapsulated sulfamethoxazole with cellulose acetate phthalate and colloidal silica, montmorillonite, or talc. J Pharm Sci 70:1256–60
   PubMed Web of Science ®Google Scholar
• Tan EY, Hartmann G, Chen Q, et al. (2010). Pharmacokinetics, metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in rats and rhesus monkeys. Drug Metab Dispos 38:459–73
   PubMed Web of Science ®Google Scholar