Division of Medicinal Chemistry Abstracts-235th ACS National ...

experimental evidence. We discuss their relevance for IN inhibitor design, in particular for the
development of strand transfer inhibitors, and report on published applications of these models
to computer-aided drug design projects.
MEDI 7
Design of a novel biphenyl class of CETP inhibitors
Zhijian Lu 1 , Joann B. Napolitano 1 , Ashleigh Theberge 1 , Milton L. Hammond 1 , Eugene Tan 1 ,
Xinchun Tong 1 , Suoyu S. Xu 1 , Melanie J. Latham 2 , Laurence B. Peterson 2 , Matt S. Anderson 3 ,
Suzanne S. Eveland 3 , Qiu Guo 3 , Sheryl A. Hyland 3 , Denise P. Milot 3 , Ying Chen 3 , Carl P.
Sparrow 3 , Samuel D. Wright 3 , and Peter J. Sinclair 1 . (1) Department of Medicinal Chemistry,
Merck Research Laboratories, Rahway, NJ 07065, Fax: 732-594-4392, zhijian_lu@merck.com,
(2) Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, (3)
Department of Atherosclerosis and Endocrinology, Merck Research Laboratories, Rahway, NJ
07065
Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and
peripheral vascular disease, represent a truly enormous burden to the health care systems of
the industrialized world. Metabolic control of lipoprotein levels is a complex and dynamic
process involving many factors. One important metabolic control in man is the cholesteryl ester
transfer protein (CETP), a plasma glycoprotein that catalyzes the movement of cholesteryl
esters from HDL to the apoB containing lipoproteins, especially VLDL. It has been demonstrated
that pharmacological inhibition of CETP in humans will result in increased levels of HDL-C and
decreased concentration of LDL-C. The clinical benefit, if any, of such inhibition is still unknown.
A number of CETP inhibitor scaffolds have been reported, most notably the tetrahydroquinoline
core of Pfizer's torcetrapib and the acylaminobenzenethiol core of the Roche / JTT inhibitor
R1628 (JTT-705). This presentation will discuss the design, synthesis and biological evaluation
of a novel biphenyl class of CETP inhibitor which shows potent in vitro activity and in vivo
efficacy in a CETP transgenic mouse pharmacodynamic model.
MEDI 8
DNA Ligase inhibitors identified via computational and experimental methods
Shijun Zhong 1 , Xi Chen 2 , Xiao Zhu 1 , Gerald M. Wilson 3 , Alan E. Tomkinson 2 , and Alexander D.
MacKerell 1 . (1) Department of Pharmaceutical Sciences, School of Pharmacy, University of
Maryland, 20 Penn St, Baltimore, MD 21201, Fax: 410-706-5017, szhong@rx.umaryland.edu,
(2) Radiation Oncology Research Laboratory, Department of Radiation Oncology, School of
Medicine, University of Maryland, Baltimore, MD 21201, (3) Department of Biochemistry and
Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201
DNA ligase functions in both DNA replication and repair by linking together DNA strands that
have either single- or doubled-strand breaks. Inhibition of DNA ligase may, therefore, be of
therapeutic utility for the treatment of cancer as an enhancer of radiation therapy. A molecular
dynamics (MD) simulation was applied to generate multiple protein conformations of human
DNA Ligase I (hLigI) to address the flexibility of the protein. Database screening of over 1 million