Gayle E. Taylor

Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to the Discovery of Anacetrapib

The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.

Design and synthesis of novel antibacterial agents with inhibitory activity against DNA polymerase III.

4-Substituted 2-amino-6-(anilino)pyrimidines have been found to be selective inhibitors of DNA polymerase III, a replicative enzyme known to be essential in the DNA synthesis of Gram-positive bacteria. Among the analogues, 18 displayed an IC(50) of 10 microM against DNA polymerase III from Staphylococcus aureus.

Discovery of betamethasone 17α-carbamates as dissociated glucocorticoid receptor modulators in the rat

A series of betamethasone 17alpha-carbamates were designed, synthesized, and evaluated for their ability to dissociate the two main functions of the glucocorticoid receptor, that is, transactivation and transrepression, in rat cell lines. A number of alkyl substituted betamethasone 17alpha-carbamates were identified with excellent affinity for the glucocorticoid receptor (e.g., 7, GR IC(50) 5.1 nM) and indicated dissociated profiles in functional assays of transactivation (rat tyrosine aminotransferase, TAT, and rat glutamine synthetase, GS) and transrepression (human A549 cells, MMP-1 assay). Gratifyingly, the in-vivo profile of these compounds, for example, 7, also indicated potent anti-inflammatory activity with impaired effects on glucose, insulin, triglycerides, and body weight. Taken together, these results indicate that dissociated glucocorticoid receptor modulators can be identified in rodents.

SAR studies on the central phenyl ring of substituted biphenyl oxazolidinone-potent CETP inhibitors

SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF(3) derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (>20mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.

Development of DNA polymerase IIIC inhibitors for the treatment of Gram-positive bacterial infections

Gram-positive (Gm+) bacteria express three distinct DNA polymerase-exonucleases. One of these, Gm+ DNA polymerase IIIC (DNA pol IIIC), is a highly conserved enzyme with little homology to mammalian DNA polymerase α and Gram-negative (Gm–) DNA polymerases. DNA pol IIIC has been shown to be essential in the replicative DNA synthesis of Gm+ bacteria and, as such, represents an attractive, hitherto unexploited target for antimicrobial drug development. This article briefly reviews claims for DNA pol IIIC inhibitors for the treatment of bacterial infections, registered during the period 1996 – 2004. Biological data are sparse in these patents and few claims are backed up with in vivo animal model data. Although DNA pol IIIC has clearly been validated as a bona fide target for antimicrobial drug development, the effectiveness of such an agent in the clinic, particularly against resistant strains of Gm+ bacteria, remains to be determined.