ABSTRACT
The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.
Subject(s)
Drug Discovery , Orphan Nuclear Receptors/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Dose-Response Relationship, Drug , HEK293 Cells , Hep G2 Cells , Humans , Ligands , Liver X Receptors , Male , Mice , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , BenzenesulfonamidesABSTRACT
Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.
Subject(s)
Orphan Nuclear Receptors/agonists , Protein Isoforms/agonists , Pyrroles/chemical synthesis , Binding Sites , Caco-2 Cells , Crystallography, X-Ray , Genes, Reporter , HEK293 Cells , Humans , Liver X Receptors , Orphan Nuclear Receptors/chemistry , Protein Binding , Protein Isoforms/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , TransfectionABSTRACT
The discovery and parallel synthesis of potent, small molecule antagonists of Neuromedin B receptor based on the ary-hexahydro-dibenzodiazepin-1-one core is described.
Subject(s)
Benzodiazepinones/chemical synthesis , Chemistry, Pharmaceutical/methods , Receptors, Bombesin/antagonists & inhibitors , Animals , Benzodiazepinones/pharmacology , Dose-Response Relationship, Drug , Drug Design , Electrons , Gastrin-Releasing Peptide/chemistry , HeLa Cells , Humans , Inhibitory Concentration 50 , Ligands , Models, Chemical , Peptides/chemistry , Structure-Activity RelationshipABSTRACT
The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
Subject(s)
PPAR delta/agonists , PPAR gamma/agonists , Thiazoles/chemistry , Animals , Computer Simulation , Crystallography, X-Ray , PPAR delta/metabolism , PPAR gamma/metabolism , Rats , Rats, Sprague-Dawley , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
The objective of this study was to demonstrate the efficacy of a novel peroxisome proliferator-activated receptor (PPAR) agonist and known PPARalpha and PPARdelta agonists to increase HDL-cholesterol (HDL-C) in the St. Kitts vervet, a nonhuman primate model of atherosclerosis. Four groups (n = 6) were studied and each group was assigned one of the following "treatments": a) vehicle only (vehicle); b) the PPARdelta selective agonist GW501516 (GW); c) the PPARalpha/delta agonist T913659 (T659); and d) the PPARalpha agonist TriCor (fenofibrate). No statistically significant changes were seen in body weight, total plasma cholesterol, plasma triglycerides, VLDL-C, LDL-C, or apolipoprotein B (apoB) concentrations. Each of the PPARalpha and PPARdelta agonists investigated in this study increased plasma HDL-C, apoA-I, and apoA-II concentrations and increased HDL particle size in St. Kitts vervets. The maximum percentage increase in HDL-C from baseline for each group was as follows: vehicle, 5%; GW, 43%; T659, 43%; and fenofibrate, 20%. Treatment with GW and T659 resulted in an increase in medium-sized HDL particles, whereas fenofibrate showed increases in large HDL particles. These data provide additional evidence that PPARalpha and PPARdelta agonists (both mixed and selective) have beneficial effects on HDL-C in these experimental primates.
Subject(s)
Cholesterol, HDL/blood , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Chlorocebus aethiops , Male , Particle Size , Thiazoles/pharmacologyABSTRACT
The design and parallel synthesis of potent, small molecule partial agonists of Neuromedin B receptor based on the 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide core is described.
Subject(s)
Chemistry, Pharmaceutical/methods , Indoles/chemistry , Receptors, Bombesin/agonists , Dose-Response Relationship, Drug , HeLa Cells , Humans , Indoles/pharmacology , Structure-Activity RelationshipABSTRACT
The contributions of cytochrome P450 3A (CYP3A) and P-glycoprotein to sirolimus oral bioavailability in rats were evaluated by coadministration of sirolimus (Rapamune) with the CYP3A inhibitor ketoconazole or the P-glycoprotein inhibitor D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS). Groups of six male Sprague-Dawley rats (250-300 g) were administered Rapamune (1 mg/kg) by oral gavage, alone and with ketoconazole (30 mg/kg) or TPGS (50 mg/kg). Sirolimus levels were measured in whole blood over a 6-h time course. Sirolimus C(max) (6.6 +/- 1.6 versus 26 +/- 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC(0-6)) (22 +/- 7 versus 105 +/- 27 ng. h/ml) were increased 3- to 5-fold by ketoconazole. Median T(max) (1.5-2 h) was unchanged. TPGS had no effect on sirolimus absorption. The interaction of sirolimus with P-glycoprotein was also evaluated in vitro using HCT-8 and Caco-2 cell monolayers. Consistent with published reports, sirolimus was a good inhibitor of P-glycoprotein, inhibiting polarized basolateral-to-apical flux of rhodamine 123 with an IC(50) of 0.625 to 1.25 microM (cyclosporine caused >80% inhibition at 5 microM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was <2 times the apical-to-basolateral). Moreover, sirolimus flux was not impacted by cyclosporine, suggesting that it does not undergo P-glycoprotein-mediated transport in this system. The lack of significant sirolimus transport by P-glycoprotein may, in part, explain the lack of a TPGS effect on sirolimus absorption in rats.