RESUMEN
Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were prepared and evaluated for activity against thrombin, clotting factors VIIa, IXa, Xa, and XIIa, and trypsin. The thiomorpholine analog 6 was the most active, essentially matching the thrombin inhibitory activity of 1 with slightly improved selectivity over trypsin.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Trombina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Trombina/metabolismoRESUMEN
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.
Asunto(s)
Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Cilastatina/química , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Imipenem/química , Inhibidores de beta-Lactamasas , Cilastatina/farmacología , Combinación Cilastatina e Imipenem , Cristalografía por Rayos X , Combinación de Medicamentos , Farmacorresistencia Bacteriana/efectos de los fármacos , Imipenem/farmacología , Concentración 50 Inhibidora , Klebsiella/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Biológicos , Pseudomonas/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The bridged monobactam ß-lactamase inhibitor MK-8712 (1) effectively inhibits class C ß-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C ß-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.
Asunto(s)
Antibacterianos/química , Inhibidores Enzimáticos/química , Monobactamas/síntesis química , Inhibidores de beta-Lactamasas , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Simulación por Computador , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imipenem/farmacología , Pruebas de Sensibilidad Microbiana , Monobactamas/farmacología , Estructura Terciaria de Proteína , Relación Estructura-Actividad , beta-Lactamasas/metabolismoRESUMEN
Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.
Asunto(s)
Carbapenémicos/química , Descubrimiento de Drogas/métodos , Imipenem/química , Inhibidores de beta-Lactamasas , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Carbapenémicos/farmacología , Combinación de Medicamentos , Imipenem/farmacología , Ratones , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/enzimología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Relación Estructura-Actividad , Resistencia betalactámica/efectos de los fármacos , Resistencia betalactámica/fisiología , beta-Lactamasas/metabolismoRESUMEN
The disposition and metabolism of paraherquamide (PHQ), a potent and broad-spectrum anthelminthic, were examined in sheep, dogs, and gerbils. The metabolism of PHQ in these species was extensive and marked by significant species differences both in vitro and in vivo. In sheep and gerbils, PHQ metabolism occurs mainly at the pyrrolidine moiety, generating several metabolites that, for the most part, retained nematodicidal activity in vitro. In dogs, the dioxepene group was also extensively metabolized, ultimately resulting in formation of a catechol and loss of pharmacological activity. After oral administration of [3H]PHQ to intact sheep, gerbils, and dogs, the majority of the administered radioactivity was recovered in feces. Intact PHQ accounted for 0% (dogs) to approximately 30% (sheep and gerbils) of drug-related material in feces. A detailed investigation of the composition of the intestinal content of sheep indicated that a significant amount of the dose was still present in the rumen 24 h after dose and that PHQ underwent significant dehydration in the cecum. The oral pharmacokinetic parameters of PHQ in sheep and dogs suggest that its absorption is rapid in both species but that its apparent elimination rate is significantly higher in the dog (t(1/2) approximately 1.5 h) than it is in sheep (t(1/2) approximately 8.5 h). The short elimination half-life and the absence of PHQ or other active components in the dog gastrointestinal tract provide a potential explanation of the lack of efficacy of PHQ in this species.
Asunto(s)
Indolizinas/farmacocinética , Compuestos de Espiro/farmacocinética , Administración Oral , Animales , Perros , Heces/química , Gerbillinae , Semivida , Indolizinas/administración & dosificación , Ovinos , Compuestos de Espiro/administración & dosificación , TritioRESUMEN
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).
Asunto(s)
Androstadienos/síntesis química , Androstadienos/farmacología , Receptor beta de Estrógeno/agonistas , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstadienos/química , Animales , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Receptores Androgénicos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/químicaRESUMEN
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Asunto(s)
Androstenodioles/síntesis química , Receptor beta de Estrógeno/antagonistas & inhibidores , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstenodioles/farmacología , Ciclización , Receptor beta de Estrógeno/química , Receptor beta de Estrógeno/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Asunto(s)
Androstenodiol/análogos & derivados , Androstenodiol/farmacología , Receptor beta de Estrógeno/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Androstenodiol/síntesis química , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Oxatiinas/química , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Ligandos , RatasRESUMEN
An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.
Asunto(s)
Oxatiinas/síntesis química , Receptores de Estrógenos/química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Antagonistas de Estrógenos/síntesis química , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Oxatiinas/farmacología , Ratas , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Útero/efectos de los fármacos , Útero/crecimiento & desarrolloRESUMEN
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
Asunto(s)
Oxatiinas/farmacología , Pirrolidinas/química , Receptores de Estrógenos/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Ligandos , Modelos Moleculares , Oxatiinas/química , Receptores de Estrógenos/metabolismoRESUMEN
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
Asunto(s)
Cromanos/química , Cromanos/farmacología , Receptor alfa de Estrógeno/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Sitios de Unión , Línea Celular , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Ligandos , Modelos Químicos , Estructura Molecular , Tamaño de los Órganos , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Útero/efectos de los fármacosRESUMEN
A series of 2-phenylspiroindenediones was prepared. The spiroindenediones were found to be less active than the corresponding spiroindenes as estrogen receptor ligands and failed to demonstrate the receptor subtype selectivity that had been anticipated from molecular modeling.
Asunto(s)
Indenos/química , Indenos/metabolismo , Modelos Químicos , Receptores de Estrógenos/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Sitios de Unión , Humanos , Ligandos , Modelos Moleculares , Unión ProteicaRESUMEN
A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.
Asunto(s)
Indenos/síntesis química , Indenos/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Alquilación , Animales , Borohidruros , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Clorhidrato de Raloxifeno/farmacología , Ratas , Receptores de Estrógenos/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of G6-amino derivatives of a lipophilic vancomycin analogue was prepared. Antibacterial activity of the analogues was inversely proportional to the degree of substitution of the G6-nitrogen. The fully substituted (quaternary) analogues were essentially inactive against vanA phenotype VREF strains but retained substantial activity against other bacteria, a profile reminiscent of teicoplanin.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Compuestos de Amonio Cuaternario/síntesis química , Vancomicina/análogos & derivados , Antibacterianos/química , Resistencia a Medicamentos , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincubation time-dependent, with K(I) and k(inact) values estimated at 9.9 microM and 0.16 min(-1), respectively. The observed loss of P450 3A4 activity was attenuated partially by glutathione (GSH), implying the involvement of a reactive metabolite(s) in the inactivation process. Subsequently, GSH adducts of raloxifene were identified in incubations with human liver microsomes; substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3'-position of the phenol ring, with the 7-glutathionyl derivative being most abundant based on LC/MS and NMR analyses. These adducts are postulated to derive from addition of GSH to raloxifene arene oxides followed by dehydration and aromatization. Alternatively, raloxifene may be oxidized to an extended quinone intermediate, which then is trapped by GSH conjugation. The bioactivation of raloxifene most likely is catalyzed by P450 3A4, since the formation of GSH adducts was almost abolished when liver microsomes were pretreated with ketoconazole or with an inhibitory anti-P450 3A4 IgG. The GSH adducts also were detected in incubations of raloxifene with rat or human hepatocytes, while the corresponding N-acetylcysteine adducts were identified in the bile and urine from rats treated orally with the drug at 5 mg/kg. Taken together, these data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity. The significance of these findings with respect to the clinical use of raloxifene remains to be determined.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/metabolismo , Clorhidrato de Raloxifeno/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Compuestos de Sulfhidrilo/química , Acetilcisteína/química , Animales , Citocromo P-450 CYP3A , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Cromatografía de Gases y Espectrometría de Masas , Glutatión/química , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Oxidación-Reducción , Clorhidrato de Raloxifeno/química , Clorhidrato de Raloxifeno/farmacología , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacologíaRESUMEN
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.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Ligandos , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Animales , Compuestos Bicíclicos con Puentes/farmacología , Femenino , Cinética , Modelos Moleculares , Conformación Molecular , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Útero/efectos de los fármacosRESUMEN
A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.