Diphenylpyridylethanamine (DPPE) derivatives as cholesteryl ester transfer protein (CETP) inhibitors.

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Harikrishnan LS, Finlay HJ, Qiao JX, Kamau MG, Jiang J, Wang TC, Li J, Cooper CB, Poss MA, Adam LP, Taylor DS, Chen AY, Yin X, Sleph PG, Yang RZ, Sitkoff DF, Galella MA, Nirschl DS, Van Kirk K, Miller AV, Huang CS, Chang M, Chen XQ, Salvati ME, Wexler RR, Lawrence RM

Diphenylpyridylethanamine (DPPE) derivatives as cholesteryl ester transfer protein (CETP) inhibitors.

J Med Chem. 2012 Jul 12;55(13):6162-75. doi: 10.1021/jm300611v. Epub 2012 Jun 22.

PubMed ID

22650305 [ View in PubMed

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Abstract

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Torcetrapib	Cholesteryl ester transfer protein	IC 50 (nM)	110	N/A	N/A	Details