ABSTRACT
Recently, there has been a strong interest in the ability to increase levels of high density lipoprotein-cholesterol (HDL-C). This interest stems from the hypothesis that such an elevation in HDL-C will decrease the likelihood of cardiovascular disease. Inhibition of cholesteryl ester transfer protein (CETP) has been shown to elevate HDL-C levels in human subjects. This letter describes the discovery of a novel and potent (<100 nM IC50 for the inhibition of CE transfer) CETP inhibitor scaffold containing an oxazolidinone core.
ABSTRACT
Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.
Subject(s)
Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds/chemistry , Glucocorticoids/chemistry , Pyrazoles/chemistry , Receptors, Glucocorticoid/drug effects , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Humans , Ligands , Mice , Models, Chemical , Models, Molecular , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
A series of novel ligands for the glucocorticoid receptor containing two heterocycles were synthesized. These compounds were investigated for a dissociative profile using transrepression and transactivation assays. Several compounds were tested in vivo and showed the ability to reduce inflammation in a mouse.
Subject(s)
Glucocorticoids/chemistry , Heterocyclic Compounds/chemistry , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Cell Line , Glucocorticoids/administration & dosage , Glucocorticoids/pharmacology , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/pharmacology , Humans , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Rats , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Indazoles/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Glucocorticoid/metabolism , Thiophenes/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Line , Crystallography, X-Ray , Enzyme Induction , Female , Glutamate-Ammonia Ligase/biosynthesis , Glutamate-Ammonia Ligase/genetics , Humans , Indazoles/chemistry , Indazoles/pharmacology , Interleukin-6/antagonists & inhibitors , Ligands , Mice , Mice, Inbred BALB C , Molecular Conformation , Protein Isoforms/agonists , Protein Isoforms/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Radioligand Assay , Receptors, Glucocorticoid/agonists , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tyrosine Transaminase/biosynthesis , Tyrosine Transaminase/geneticsABSTRACT
A circular dichroic (CD) excition chirality method based on host-guest chiral recognition has been developed to determine the absolute configuration of carboxylic acids with an alpha-stereogenic center; an amide C = O-->Zn coordination, identified by infrared spectroscopy and computations, is involved in this complexation.
