RESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Trombina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Trombina/metabolismoRESUMO
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.
Assuntos
Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Cilastatina/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Imipenem/química , Inibidores de beta-Lactamases , Cilastatina/farmacologia , Combinação Imipenem e Cilastatina , Cristalografia por Raios X , Combinação de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Imipenem/farmacologia , Concentração Inibidora 50 , Klebsiella/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Biológicos , Pseudomonas/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/química , Inibidores Enzimáticos/química , Monobactamas/síntese química , Inibidores de beta-Lactamases , Antibacterianos/síntese química , Antibacterianos/farmacologia , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Monobactamas/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , beta-Lactamases/metabolismoRESUMO
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.
Assuntos
Carbapenêmicos/química , Descoberta de Drogas/métodos , Imipenem/química , Inibidores de beta-Lactamases , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carbapenêmicos/farmacologia , Combinação de Medicamentos , Imipenem/farmacologia , Camundongos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/enzimologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Relação Estrutura-Atividade , Resistência beta-Lactâmica/efeitos dos fármacos , Resistência beta-Lactâmica/fisiologia , beta-Lactamases/metabolismoRESUMO
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.
Assuntos
Indolizinas/farmacocinética , Compostos de Espiro/farmacocinética , Administração Oral , Animais , Cães , Fezes/química , Gerbillinae , Meia-Vida , Indolizinas/administração & dosagem , Ovinos , Compostos de Espiro/administração & dosagem , TrítioRESUMO
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).
Assuntos
Androstadienos/síntese química , Androstadienos/farmacologia , Receptor beta de Estrogênio/agonistas , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Androstadienos/química , Animais , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Receptores Androgênicos/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/químicaRESUMO
A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Assuntos
Androstenodióis/síntese química , Receptor beta de Estrogênio/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Androstenodióis/farmacologia , Ciclização , Receptor beta de Estrogênio/química , Receptor beta de Estrogênio/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Assuntos
Androstenodiol/análogos & derivados , Androstenodiol/farmacologia , Receptor beta de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Androstenodiol/síntese química , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Moduladores Seletivos de Receptor Estrogênico/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Receptor alfa de Estrogênio/antagonistas & inibidores , Oxati-Inas/química , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Ligantes , RatosRESUMO
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.
Assuntos
Oxati-Inas/síntese química , Receptores de Estrogênio/química , Moduladores Seletivos de Receptor Estrogênico/síntese química , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Oxati-Inas/farmacologia , Ratos , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Relação Estrutura-Atividade , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimentoRESUMO
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.
Assuntos
Oxati-Inas/farmacologia , Pirrolidinas/química , Receptores de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Ligantes , Modelos Moleculares , Oxati-Inas/química , Receptores de Estrogênio/metabolismoRESUMO
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).
Assuntos
Cromanos/química , Cromanos/farmacologia , Receptor alfa de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Sítios de Ligação , Linhagem Celular , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Modelos Químicos , Estrutura Molecular , Tamanho do Órgão , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Útero/efeitos dos fármacosRESUMO
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.
Assuntos
Indenos/química , Indenos/metabolismo , Modelos Químicos , Receptores de Estrogênio/metabolismo , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Sítios de Ligação , Humanos , Ligantes , Modelos Moleculares , Ligação ProteicaRESUMO
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.
Assuntos
Indenos/síntese química , Indenos/farmacologia , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Alquilação , Animais , Boroidretos , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Cloridrato de Raloxifeno/farmacologia , Ratos , Receptores de Estrogênio/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Compostos de Amônio Quaternário/síntese química , Vancomicina/análogos & derivados , Antibacterianos/química , Resistência a Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/metabolismo , Cloridrato de Raloxifeno/metabolismo , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Compostos de Sulfidrila/química , Acetilcisteína/química , Animais , Citocromo P-450 CYP3A , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Glutationa/química , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Oxirredução , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , Ratos , Ratos Sprague-Dawley , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologiaRESUMO
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.
Assuntos
Compostos Bicíclicos com Pontes/química , Ligantes , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Animais , Compostos Bicíclicos com Pontes/farmacologia , Feminino , Cinética , Modelos Moleculares , Conformação Molecular , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Relação Estrutura-Atividade , Útero/efeitos dos fármacosRESUMO
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.