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

Xenobiotica. 2014 Jul;44(7):591-605. doi: 10.3109/00498254.2013.874611. Epub 2013 Dec 31.


1. Elaborate studies of cholesteryl ester transfer protein (CETP) polymorphisms and genetic deficiency in humans suggest direct links between CETP, high-density lipoprotein cholesterol (HDL-c) levels and coronary heart diseases. The hypothesis that CETP inhibition by small molecule inhibitors raises HDL-c has been validated clinically with structurally-diverse CETP inhibitors such as torcetrapib, anacetrapib, dalcetrapib and evacetrapib. 2. Despite promising phase 2 results with respect to HDL-c elevation, torcetrapib was discontinued in phase 3 trials due to increased mortality rates in the cardiovascular outcomes study. Emerging evidence for the adverse effects hints at off-target chemotype-specific cardiovascular toxicity, possibly related to the pressor effects of torcetrapib, since structurally diverse CETP inhibitors such as anacetrapib, evacetrapib and dalcetrapib are not associated with blood pressure increases in humans. Nonclinical follow-up studies showed that torcetrapib induces aldosterone biosynthesis and secretion in vivo and in vitro, an effect which is not observed with other CETP inhibitors in clinical development. 3. As part of ongoing efforts to identify novel CETP inhibitors devoid of pressor effects, strategies were implemented towards the design of compounds, which lack the 1,2,3,4-tetrahydroquinoline (THQ) scaffold present in torcetrapib. In this article, we disclose results of structure-activity relationship studies for a series of novel non-THQ CETP inhibitors, which resulted in the identification of a novel isonipecotic acid derivative 10 (also referred to as PF-04445597) with vastly improved oral pharmacokinetic properties mainly as a result of improved aqueous solubility. This feature is attractive in that, it bypasses significant investments needed to develop compatible solubilizing formulation(s) for oral drug delivery of highly lipophilic and poorly soluble compounds; attributes, which are usually associated with small molecule CETP inhibitors. PF-04445597 was also devoid of aldosterone secretion in human H295R adrenal carcinoma cells.

Keywords: CETP; CYP; formulation; human; inhibitor; oral bioavailability; pharmacokinetics.

MeSH terms

  • Administration, Oral
  • Aldosterone / metabolism
  • Animals
  • Anticholesteremic Agents / chemistry*
  • Anticholesteremic Agents / pharmacokinetics
  • Anticholesteremic Agents / pharmacology*
  • Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
  • Cytochrome P-450 CYP3A Inhibitors / chemistry
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Drug Design
  • Drug Evaluation, Preclinical / methods*
  • Female
  • Humans
  • Injections, Intravenous
  • Isonipecotic Acids / chemistry
  • Isonipecotic Acids / pharmacology
  • Macaca fascicularis
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Quinolines / chemistry*
  • Quinolines / pharmacology
  • Rats, Sprague-Dawley
  • Solubility
  • Structure-Activity Relationship


  • Anticholesteremic Agents
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Cytochrome P-450 CYP3A Inhibitors
  • Isonipecotic Acids
  • PF-04445597
  • Quinolines
  • Aldosterone
  • torcetrapib