ABSTRACT
ß-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C ß-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C ß-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
Subject(s)
Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Cilastatin/chemistry , Drug Discovery , Enzyme Inhibitors/chemistry , Imipenem/chemistry , beta-Lactamase Inhibitors , Cilastatin/pharmacology , Cilastatin, Imipenem Drug Combination , Crystallography, X-Ray , Drug Combinations , Drug Resistance, Bacterial/drug effects , Imipenem/pharmacology , Inhibitory Concentration 50 , Klebsiella/drug effects , Microbial Sensitivity Tests , Models, Biological , Pseudomonas/drug effects , Structure-Activity RelationshipABSTRACT
A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Subject(s)
Androstadienes/chemical synthesis , Androstadienes/pharmacology , Estrogen Receptor beta/agonists , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Androstadienes/chemistry , Animals , Binding Sites/drug effects , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Receptors, Androgen/drug effects , Selective Estrogen Receptor Modulators/chemistryABSTRACT
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Subject(s)
Androstenediols/chemical synthesis , Estrogen Receptor beta/antagonists & inhibitors , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Androstenediols/pharmacology , Cyclization , Estrogen Receptor beta/chemistry , Estrogen Receptor beta/metabolism , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Subject(s)
Androstenediol/analogs & derivatives , Androstenediol/pharmacology , Estrogen Receptor beta/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Androstenediol/chemical synthesis , Crystallography, X-Ray , Humans , Ligands , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Ligands , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Animals , Bridged Bicyclo Compounds/pharmacology , Female , Kinetics , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
Directed screening of metalloprotease inhibitors identified CGS 30084 (1) as a potent inhibitor of endothelin-converting enzyme-1 (ECE-1) in vitro (IC(50)=77 nM). Herein we report the syntheses and biological activities of analogues containing modified biphenyl moieties, bearing heterocyclic proximal rings. Compound 20, the thioacetate ethyl ester prodrug derivative of compound 19a, was found to be an orally active and potent inhibitor of ECE-1 activity in rats.
