RESUMEN
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.
Asunto(s)
Receptor beta de Estrógeno/efectos de los fármacos , Fluorenos/química , Pirazoles/química , Animales , Área Bajo la Curva , Disponibilidad Biológica , Ciclización , Receptor beta de Estrógeno/metabolismo , Fluorenos/sangre , Fluorenos/metabolismo , RatasRESUMEN
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.
Asunto(s)
Receptor beta de Estrógeno/efectos de los fármacos , Fluorenos/síntesis química , Fluorenos/farmacología , Línea Celular , Cristalografía por Rayos X , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/efectos de los fármacos , Receptor beta de Estrógeno/química , Fluorenos/clasificación , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Proteínas Bacterianas , Carbapenémicos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Hexosiltransferasas , Peptidil Transferasas , Carbapenémicos/química , Carbapenémicos/farmacología , Proteínas Portadoras/efectos de los fármacos , Proteínas Portadoras/metabolismo , Farmacorresistencia Microbiana , Pruebas de Sensibilidad Microbiana , Muramoilpentapéptido Carboxipeptidasa/efectos de los fármacos , Muramoilpentapéptido Carboxipeptidasa/metabolismo , Proteínas de Unión a las PenicilinasRESUMEN
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.
Asunto(s)
Carbapenémicos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Lactamas/farmacología , Tiazoles/farmacología , Animales , Carbapenémicos/química , Carbapenémicos/farmacología , Carbapenémicos/toxicidad , Farmacorresistencia Microbiana , Humanos , Lactamas/química , Lactamas/farmacocinética , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinéticaRESUMEN
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.
Asunto(s)
Proteínas Bacterianas , Carbapenémicos/inmunología , Carbapenémicos/farmacología , Diseño de Fármacos , Hexosiltransferasas , Lactamas/farmacología , Peptidil Transferasas , Tiazoles/farmacología , Animales , Anticuerpos/sangre , Carbapenémicos/química , Carbapenémicos/metabolismo , Carbapenémicos/toxicidad , Proteínas Portadoras/metabolismo , Dipeptidasas/metabolismo , Farmacorresistencia Microbiana , Resistencia a Múltiples Medicamentos , Enterococcus/efectos de los fármacos , Eritrocitos/inmunología , Haptenos , Humanos , Epítopos Inmunodominantes , Inmunoglobulina G/sangre , Lactamas/síntesis química , Lactamas/química , Lactamas/metabolismo , Activación de Linfocitos , Macaca mulatta , Ratones , Ratones Endogámicos DBA , Pruebas de Sensibilidad Microbiana , Muramoilpentapéptido Carboxipeptidasa/metabolismo , Proteínas de Unión a las Penicilinas , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus/efectos de los fármacos , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/metabolismoRESUMEN
The syntheses of five thiols, including three dihydropyrrolotriazoliumthiol salts, 1,4-dimethyl-5-mercaptomethyl-1,2,4-triazolium trifluoromethanesulfonate, and 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride; and the addition of these thiols to 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-met hylcarbapen-2-em-3-carboxylate and the subsequent hydrogenolysis of the addition products is described. The latter thiol provides a new route towards the preparation of L-627 (LJC 10,627). The compounds were evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria and their antibacterial activities compared with imipenem. The compounds were measured for their hydrolytic stability to dehydropeptidase I (DHP-I) relative to imipenem. The five compounds generally had poorer Gram-positive and Pseudomonas activity than imipenem, although their Gram-negative activity was variably improved. The monocyclic triazolium analog was nearly comparable in overall activity to the four bicyclic heterarylium analogs evaluated, including L-627 (LJC 10,627). All compounds were more stable to DHP-I than imipenem, although minor differences existed among them.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Antibacterianos/metabolismo , Carbapenémicos/metabolismo , Dipeptidasas/metabolismo , Estabilidad de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Tienamicinas/síntesis química , Tienamicinas/farmacologíaRESUMEN
delta 1-Thienamycin (2), a double-bond isomer of thienamycin, was prepared by isomerizing N-[[(p-nitrobenzyl)oxy]-carbonyl]thienamycin p-nitrobenzyl ester (5b) with DBU in Me2SO followed by hydrogenolysis of the protecting groups. When evaluated in a disc-diffusion antibacterial assay, delta 1-thienamycin was found to be essentially devoid of activity. The lack of antibacterial activity was ascribed to a chemically less reactive beta-lactam amide bond than that found in thienamycin.
Asunto(s)
Lactamas/síntesis química , Tienamicinas , Bacterias/efectos de los fármacos , Fenómenos Químicos , Química , Lactamas/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
A versatile stereocontrolled total synthesis of thienamycin starting from L-aspartic acid is reported. Stereocontrol is achieved by potassium tri-sec-butylborohydride reduction of a thermodynamically formed 3 alpha-acetylazetidinone intermediate. The key [3.2.0] bicyclic ring system is prepared by a metal catalyzed carbene insertion reaction.