Subject(s)
Biphenyl Compounds/pharmacology , Histamine Antagonists/pharmacology , Nitriles/pharmacology , Obesity/metabolism , Obesity/prevention & control , Pyrrolidines/pharmacology , Receptors, Histamine H3/metabolism , Animals , Biphenyl Compounds/adverse effects , Biphenyl Compounds/chemistry , Diet , Dietary Fats/administration & dosage , Dietary Fats/pharmacology , Histamine Agonists/chemistry , Histamine Agonists/pharmacology , Histamine Antagonists/adverse effects , Histamine Antagonists/chemistry , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Nitriles/adverse effects , Nitriles/chemistry , Obesity/chemically induced , Pyrrolidines/adverse effects , Pyrrolidines/chemistryABSTRACT
The preparation and characterization of a series of selective glucocorticoid receptor modulators are described. The preliminary structure-activity relationship of nonaromatic C-5 substitution on the tetracyclic quinoline core showed a preference for small lipophilic side chains. Proper substitution at this position maintained the transcriptional repression of proinflammatory transcription factors while diminishing the transcriptional activation activity of the ligand/glucocorticoid receptor complex. The optimal compounds described in this study were the allyl analogue 18 and cyclopentyl analogue 32. These candidates showed slightly less potent, highly efficacious E-selectin repression with significantly reduced levels of glucocorticoid response element activation in reporter gene assays vs prednisolone. Allyl analogue 18 was evaluated in vivo. An oral dose of 18 showed an ED(50) = 1.7 mg/kg as compared to 1.2 mg/kg for prednisolone in the Sephadex-induced pulmonary eosinophilia model and an ED(50) = 15 mg/kg vs 4 mg/kg for prednisolone in the carrageenan-induced paw edema model.
Subject(s)
Benzopyrans/chemical synthesis , Quinolines/chemical synthesis , Receptors, Glucocorticoid/drug effects , Animals , Benzopyrans/chemistry , Benzopyrans/pharmacology , Binding, Competitive , Carrageenan , Cell Line , Chlorocebus aethiops , Depression, Chemical , E-Selectin/genetics , E-Selectin/metabolism , Edema/chemically induced , Edema/pathology , Eosinophils/pathology , Genes, Reporter , Humans , Insecta , Luciferases/genetics , Luciferases/metabolism , Male , NF-kappa B/genetics , NF-kappa B/metabolism , Pneumonia/pathology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/genetics , Response Elements , Structure-Activity Relationship , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Transcription, Genetic/drug effectsABSTRACT
A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.
Subject(s)
Adenosine Kinase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyrimidines/pharmacology , Adenosine Kinase/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Conformation , Morpholines/chemistry , Morpholines/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
