Identification of a potent and metabolically stable series of fluorinated diphenylpyridylethanamine-based cholesteryl ester transfer protein inhibitors

Michael M Miller; Yalei Liu; Ji Jiang; James A Johnson; Muthoni Kamau; David S Nirschl; Yufeng Wang; Lalgudi Harikrishnan; David S Taylor; Alice Ye A Chen; Xiaohong Yin; Ramakrishna Seethala; Tara L Peterson; Tatyana Zvyaga; Jun Zhang; Christine S Huang; Ruth R Wexler; Michael A Poss; R Michael Lawrence; Leonard P Adam; Mark E Salvati

doi:10.1016/j.bmcl.2012.08.011

Identification of a potent and metabolically stable series of fluorinated diphenylpyridylethanamine-based cholesteryl ester transfer protein inhibitors

Bioorg Med Chem Lett. 2012 Oct 15;22(20):6503-8. doi: 10.1016/j.bmcl.2012.08.011. Epub 2012 Aug 9.

Affiliation

¹ Discovery Chemistry, Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA. michael.miller@bms.com

PMID: 22995620
DOI: 10.1016/j.bmcl.2012.08.011

Abstract

A novel series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein is described. Optimization of the urea moiety, particularly by incorporation of fluorine, is explored to balance in vitro metabolic stability with CETP potency in the whole plasma assay.

MeSH terms

Amines / blood
Amines / chemistry
Amines / metabolism
Amines / pharmacology
Animals
Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
Cholesterol Ester Transfer Proteins / metabolism
Halogenation
Humans
Mice
Pyridines / blood
Pyridines / chemistry*
Pyridines / metabolism
Pyridines / pharmacology*
Rats
Urea / analogs & derivatives*
Urea / blood
Urea / metabolism
Urea / pharmacology*

Substances

Amines
Cholesterol Ester Transfer Proteins
Pyridines
Urea