ABSTRACT
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.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Oxazolidinones/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Cholesterol, HDL/metabolism , Dose-Response Relationship, Drug , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Mice, Transgenic , Models, Chemical , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Oxazolidinones/chemical synthesis , Animals , Cholesterol Ester Transfer Proteins/chemistry , Cholesterol, HDL/blood , Humans , Macaca fascicularis , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oxazolidinones/pharmacokinetics , Oxazolidinones/pharmacology , Recombinant Proteins/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Betamethasone/analogs & derivatives , Carbamates/chemical synthesis , Receptors, Glucocorticoid/metabolism , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Betamethasone/chemical synthesis , Betamethasone/pharmacokinetics , Betamethasone/pharmacology , Blood Glucose/metabolism , Body Weight/drug effects , Carbamates/chemistry , Carbamates/pharmacokinetics , Carbamates/pharmacology , Glutamate-Ammonia Ligase/metabolism , Insulin/blood , Liver/drug effects , Liver/metabolism , Matrix Metalloproteinase 1/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Rats , Receptors, Glucocorticoid/chemistry , Triglycerides/blood , Tyrosine Transaminase/metabolismABSTRACT
6-Anilinopyrazolo[3,4-d]pyrimidin-4-ones are novel dGTP analogues that inhibit the replication-specific enzyme DNA polymerase III (DNA pol III) of Staphlococcus aureus and other Gram-positive (Gr+) bacteria. To enhance the potential of these inhibitors as antimicrobial agents, a structure-activity relationship was developed involving substitutions at the 2, 4, and pyrazolo NH positions. All of the new inhibitors were tested for their ability to inhibit S. aureus DNA pol III and the growth of several other Gr+ bacteria in culture. 2-Anilino groups with small hydrophobic groups in the meta or para position enhanced both antipolymerase and antimicrobial activity. 2-Benzyl-substituted inhibitors were substantially less active. Substitution in the 4-position by oxygen gave the optimal activity, whereas substitution at the pyrazolo NH was not tolerated. These pyrazolo[3,4-d]pyrimidine derivatives represent a novel class of antimicrobials with promising activities against Gr+ bacteria.
