Dalcetrapib (JTT-705, RO4607381)

IC50: 6 μM for CETP inhibition in human plasma

Cholesteryl ester transfer protein (CETP) is a plasma protein that transfers neutral lipids among the lipoproteins. Its most important action is the exchange of cholesteryl esters in high-density lipoprotein (HDL) for triglycerides in very low-density lipoprotein. Thus, CETP is a potentially atherogenic protein, and its atherogenicity has been supported by many studies. Dalcetrapib is a novel inhibitors of CETP.

In vitro: Dalcetrapib achieved 50% inhibition of CETP activity in human plasma at a concentration of 6 μM. The mechanism of action was considered to involve the formation of a disulfide bond between the thiol form of Dalcetrapib and the cysteine residue at position 13 (Cys13) of CETP. [1].

In vivo: Dalcetrapib achieved 95% inhibition of CETP activity in male Japanese white rabbits at an oral dose of 30 mg/kg. It increased the plasma HDL cholesterol level by 27% and 54%, respectively, when given at oral doses of 30 or 100 mg/kg once a day for 3 days to male Japanese white rabbits [1].

Clinical trials: In a phase II study, Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed [2].

References:
[1] Shinkai H, Maeda K, Yamasaki T, Okamoto H, Uchida I.  bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein. J Med Chem. 2000;43(19):3566-72.
[2] Fayad ZA, Mani V, Woodward M, Kallend D, Abt M, Burgess T, Fuster V, Ballantyne CM, Stein EA, Tardif JC, Rudd JH, Farkouh ME, Tawakol A.   Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378(9802):1547-59.

Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial.[Pubmed:20097702]

Eur Heart J. 2010 Feb;31(4):480-8.

AIMS: Co-primary objectives were to evaluate dalcetrapib (JTT-705/RO4607381), which targets cholesteryl ester transfer protein (CETP), effects on high-density lipoprotein cholesterol (HDL-C) in participants with coronary heart disease or risk equivalents and to evaluate potential changes in mesenteric lymph nodes. METHODS AND RESULTS: Double-blind trial with participants randomized (2:1) to dalcetrapib 900 mg/day (higher than 600 mg phase III dose) or placebo, both with atorvastatin, for 24 weeks (n = 135; one without post-baseline efficacy data was excluded from intent-to-treat population); a subset continued for 24-week extension (n = 77). Lipid changes and safety parameters were assessed. Mesenteric lymph nodes were evaluated by magnetic resonance imaging. Dalcetrapib increased HDL-C (33.4%, Week 24; 33.8%, Week 48), decreased CETP activity (-53.5%, Week 24; -56.5%, Week 48), and increased apolipoprotein A-I (11.4%, Week 24; 16.4%, Week 48). Dalcetrapib showed no clinically relevant differences vs. placebo in adverse events, laboratory parameters including aldosterone, electrocardiograms, and vital signs including blood pressure (BP). Dalcetrapib had no measurable, clinically relevant effect on lymph node size. CONCLUSION: Dalcetrapib 900 mg administered for up to 48 weeks showed no clinically relevant changes in lymph nodes, BP, or other safety parameters. Dalcetrapib effectively increased HDL-C over 48 weeks of treatment.

Dalcetrapib: JTT 705; JTT-705; R 1658; R1658; RG1658; RO 4607381; RO4607381.[Pubmed:20509713]

Drugs R D. 2010;10(1):33-6.

Roche and Japan Tobacco are in a licensing agreement to develop and commercialize dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor to slow or prevent atherosclerosis. This drug is currently in phase III development. This review discusses the development history and scientific profile of this new compound.