ABSTRACT
Synthesis of a series of fused pyrazole tetrahydrofluorenone analogs which are potent, ERbeta subtype selective ligands is described. Analogs possessing subnanomolar ERbeta binding, greater than 100-fold ERbeta-selectivity, and oral bioavailability are reported.
Subject(s)
Estrogen Receptor beta/drug effects , Fluorenes/chemistry , Pyrazoles/chemistry , Animals , Area Under Curve , Biological Availability , Cyclization , Estrogen Receptor beta/metabolism , Fluorenes/blood , Fluorenes/metabolism , RatsABSTRACT
Synthesis and derivatization of a series of substituted tetrahydrofluorenone analogs giving potent, ERbeta subtype selective ligands are described. Several analogs possessing ERbeta binding affinities comparable to 17beta-estradiol but with greater than 75-fold selectivity over ERalpha are reported.
Subject(s)
Estrogen Receptor beta/drug effects , Fluorenes/chemical synthesis , Fluorenes/pharmacology , Cell Line , Crystallography, X-Ray , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/drug effects , Estrogen Receptor beta/chemistry , Fluorenes/classification , Humans , Ligands , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.
Subject(s)
Bacterial Proteins , Carbapenems/chemical synthesis , Gram-Positive Bacteria/drug effects , Hexosyltransferases , Peptidyl Transferases , Carbapenems/chemistry , Carbapenems/pharmacology , Carrier Proteins/drug effects , Carrier Proteins/metabolism , Drug Resistance, Microbial , Microbial Sensitivity Tests , Muramoylpentapeptide Carboxypeptidase/drug effects , Muramoylpentapeptide Carboxypeptidase/metabolism , Penicillin-Binding ProteinsABSTRACT
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.
Subject(s)
Carbapenems/chemical synthesis , Gram-Positive Bacteria/drug effects , Lactams/pharmacology , Thiazoles/pharmacology , Animals , Carbapenems/chemistry , Carbapenems/pharmacology , Carbapenems/toxicity , Drug Resistance, Microbial , Humans , Lactams/chemistry , Lactams/pharmacokinetics , Mice , Microbial Sensitivity Tests , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.
