RESUMO
The synthesis of 17-epi-ethynylestradiol (10), the 17 beta-ethynyl-17 alpha-ol epimer of the well-known orally active estrogen, ethynylestradiol (1), was achieved by LiA1H4 reduction of epoxide 9, as well as by demethylating epimestranol (11) with CH3MgI. Compound 11 was obtained by the unusual 17 beta-ethynylation of estrone 3-methyl ether 22 under equilibrating conditions. The in vitro estrogen receptor-binding affinity and the oral estrogenicity in the rat for the 17-epi compounds 10, 11 and 20 (epiquinestrol) was evaluated. Despite moderate estrogen receptor-binding affinity, compound 10 was devoid of measurable estrogenicity at 10 mg/kg or antiestrogenicity at 3 mg/kg.
Assuntos
Etinilestradiol/análogos & derivados , Etinilestradiol/síntese química , Mestranol/síntese química , Norpregnatrienos/síntese química , Quinestrol/síntese química , Animais , Antagonistas de Estrogênios/síntese química , Etinilestradiol/metabolismo , Etinilestradiol/farmacologia , Feminino , Técnicas In Vitro , Mestranol/metabolismo , Mestranol/farmacologia , Quinestrol/metabolismo , Quinestrol/farmacologia , Coelhos , Ratos , Receptores de Estrogênio/metabolismo , Estereoisomerismo , Útero/efeitos dos fármacos , Vagina/efeitos dos fármacosRESUMO
The 17alpha-ethyl-substituted analogs of the two epimeric 20-dihydroprogesterones, allopregnadedione and pregn-5-ene-3,20-dione, were synthesized and evaluated for their possible oral contragestational (postcoital antifertility) activity in the rat. The compounds, though bound strongly to the progesterone receptor in vitro, were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.
PIP: 17alpha-20alpha- and 20beta-dihydroprogesterones and other 17alpha-ethyl-substituted pregnanes as potential contragestational agents were investigated in the rat, and the syntheses of 17 alpha-ethyl-substituted analogs of the 2 epimeric 20-dihydroprogesterones, allopregnanedione and pregn-5-ene-3,20 dione are presented. The compounds were administered orally to 5 rats on Days 1-6 of gestation for studies related to effects on implantation or on Days 9-12 of gestation for studies related to drug effects on pregnancy after implantation. Postmortem examination was carried out between Day 14 and Day 21 of gestation. The compounds were strongly bound to the pr ogesterone receptor in vitro but were inactive preimplantively at 10 mg/kg and postimplantively at 40 mg/kg in vivo.
Assuntos
20-alfa-Di-Hidroprogesterona , Anticoncepcionais Sintéticos Pós-Coito/síntese química , Anticoncepcionais Pós-Coito/síntese química , Pregnanos/síntese química , Progesterona/análogos & derivados , 20-alfa-Di-Hidroprogesterona/análogos & derivados , 20-alfa-Di-Hidroprogesterona/síntese química , 20-alfa-Di-Hidroprogesterona/metabolismo , 20-alfa-Di-Hidroprogesterona/farmacologia , Animais , Anticoncepcionais Sintéticos Pós-Coito/metabolismo , Anticoncepcionais Sintéticos Pós-Coito/farmacologia , Implantação do Embrião/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Idade Gestacional , Pregnanos/metabolismo , Pregnanos/farmacologia , Ratos , Receptores de Superfície Celular , EstereoisomerismoRESUMO
A series of isoquinolin-3-ol derivatives (II) was prepared as analogues of the clinical cardiotonic agent bemarinone (ORF 16600, I). Although in many respects the structural requirements for the cardiotonic activity of II are similar to those of bemarinone, certain differences between the series were noted. Our structure-activity studies show that II is less sensitive to alkoxy-substitution effects than is I, and more significantly, 4-substitution of II by alkyl groups, halogen, or alkanecarboxylic acid derivatives enhances cardiotonic activity in II in contrast to I, wherein analogous substitution eliminated activity. A linear correlation between contractile force (CF) increase and cyclic nucleotide phosphodiesterase fraction III (PDE-III) inhibition by the title compounds was determined. The isoquinoline derivatives were characteristically short-acting cardiotonic agents with good potency and selectivity.
Assuntos
Isoquinolinas/síntese química , Contração Miocárdica/efeitos dos fármacos , Quinazolinas/síntese química , Animais , Pressão Sanguínea/efeitos dos fármacos , Fenômenos Químicos , Química , Cães , Frequência Cardíaca/efeitos dos fármacos , Isoquinolinas/farmacologia , Cinética , Inibidores de Fosfodiesterase/farmacologia , Quinazolinas/farmacologia , Estimulação Química , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacosRESUMO
The synthesis of and guinea pig contragestational screening data for several oxepane and 3,8-dioxabicyclo[3.2.1]octane analogues of zoapatanol (1) are described and their structure-activity relationships discussed. Conversion of the 5-keto group on the nonenyl side chain of 1 into a hydroxyl function enhanced the potency. Further significant enhancement in the potency was realized with the transformation of several oxepanes into the 3,8-dioxabicyclo-[3.2.1]octane-1-acetic acid derivatives. Detailed, comparative contragestational evaluation of the three most potent compounds 9, 33, and 37 is presented, which led to the selection of 33 (ORF 13811) for further biological evaluation.
Assuntos
Abortivos não Esteroides/síntese química , Abortivos/síntese química , Oxepinas/farmacologia , Abortivos não Esteroides/farmacologia , Animais , Feminino , Cobaias , Montanoa , Gravidez , Relação Estrutura-AtividadeRESUMO
The synthesis and cardiovascular evaluation of a series of isoquinolin-3-ol derivatives bearing a variety of nitrogen substituents (amino, acylamino, carbamate, and ureido) at C-4 are described. Certain of these compounds have a selective renal vasodilating profile and have minimal effects on arterial blood pressure or heart rate when administered intravenously in the instrumented anesthetized dog. The most potent renal vasodilator in the series is 4-(allylureido)-6,7-dimethoxyisoquinolin-3-ol (38), which at a dose of 1.2 mg/kg iv produces a 97% maximal increase in renal blood flow without significant hypotensive or chronotropic effects. Structure-activity observations on the nature of the 4-substituent and the alkoxy substitution pattern in the aromatic ring of the isoquinolinol nucleus are discussed.
Assuntos
Isoquinolinas/farmacologia , Circulação Renal/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Frequência Cardíaca/efeitos dos fármacos , Relação Estrutura-Atividade , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/síntese químicaRESUMO
The synthesis, cardiac fraction III cyclic nucleotide phosphodiesterase (PDE-III) inhibition, and positive inotropic activity of a series of 2(1H)-quinazolinones are reported. A general synthesis of the series involved the cyclization of 2-aminoacetophenones with potassium cyanate in acetic acid. Modifications at the 4-position of the quinazoline nucleus were best achieved by formation of the intermediate N1-acyl-N3-phenylurea from the substituted phenyl isocyanate and appropriate carboxamide. PPA was used to ring close to the quinazoline product. Generally the SAR for the series paralleled the five-point model previously published for PDE-III inhibition. The most active analogue of the series was 5,6-dimethoxy-4-methyl-2(1H)-quinazolinone (1) (ORF 16600), which had about twice the intravenous potency of amrinone. Compound 1 is currently under development as an orally active cardiotonic.
Assuntos
Contração Miocárdica/efeitos dos fármacos , Quinazolinas/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Fenômenos Químicos , Química , Cães , Frequência Cardíaca/efeitos dos fármacos , Miocárdio/enzimologia , Quinazolinas/síntese química , Estimulação Química , Relação Estrutura-AtividadeRESUMO
A series of purine derivatives was prepared and examined for selective inotropic activity in vitro and in vivo. Thioether-linked derivatives were superior to their oxygen and nitrogen isosteres. Substitution of electron-withdrawing groups on the benzhydryl moiety of these agents increased potency. The best compound of the study, 17 (carsatrin), was examined further and demonstrated selective oral activity as a positive inotrope. These compounds are presumed to act by affecting the kinetics of the cardiac sodium channel by analogy to the prototypic agent DPI 201106 (1). Their high selectivity for increasing contractile force and dP/dt without affecting blood pressure or heart rate is consistent with this mechanism. Carsatrin (17) was selected as a potential development candidate.
Assuntos
Cardiotônicos/síntese química , Cardiotônicos/farmacologia , Mercaptopurina/análogos & derivados , Contração Miocárdica/efeitos dos fármacos , Piperazinas/síntese química , Purinas/síntese química , Purinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Furões , Frequência Cardíaca/efeitos dos fármacos , Masculino , Mercaptopurina/síntese química , Mercaptopurina/farmacologia , Estrutura Molecular , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Piperazinas/farmacologia , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/fisiologia , Estimulação Química , Relação Estrutura-AtividadeRESUMO
A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 µM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores de Proteínas Quinases , Salicilanilidas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus subtilis/enzimologia , Bacillus subtilis/metabolismo , Bacillus subtilis/fisiologia , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/enzimologia , Enterococcus faecium/genética , Enterococcus faecium/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Positivas/enzimologia , Bactérias Gram-Positivas/fisiologia , Luciferases/genética , Luciferases/metabolismo , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Fosforilação , Proteínas Quinases/genética , Salicilanilidas/química , Salicilanilidas/farmacologia , Esporos Bacterianos/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Vancomicina/farmacologiaRESUMO
The synthesis of 2-hydroxy and 4-hydroxymestranol by oxidation of mestranol with m-chloroperbenzoic acid is described. The oral estrogenicity and contragestational activity of these and related catechol estrogen derivatives in the rat is also presented.
Assuntos
Mestranol/análogos & derivados , Animais , Bioensaio , Feminino , Mestranol/síntese química , Mestranol/farmacologia , Métodos , Ratos , Relação Estrutura-Atividade , Útero/efeitos dos fármacosAssuntos
Abortivos/isolamento & purificação , Anticoncepcionais Femininos/isolamento & purificação , Oxepinas/análise , Oxepinas/farmacologia , Plantas Medicinais/análise , Abortivos/história , Abortivos/farmacologia , Animais , Química , Anticoncepcionais Femininos/história , Anticoncepcionais Femininos/farmacologia , Cricetinae , Relação Dose-Resposta a Droga , Feminino , Cobaias , História do Século XVI , História do Século XX , Humanos , Medicina Tradicional , México , Camundongos , Montanoa , Gravidez , RatosRESUMO
The synthesis and in vitro Class III antiarrhythmic activity of several 4-aroyl (and aryl)-1-aralkylpiperazine and piperidine derivatives are described. Among several potent compounds identified in the series, RWJ-28810 (3), with its EC20 of 3 nM, ranks as one of the most potent (in vitro) compounds reported.
Assuntos
Antiarrítmicos/síntese química , Piperazinas/farmacologia , Animais , Antiarrítmicos/farmacologia , Bioensaio , Furões , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Piperazinas/síntese química , Piperidinas/síntese química , Piperidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 6-oxa isosteres of anacardic acids (6-higher alkyl/alkenyl-2-hydroxybenzoic acids) was synthesised and several members were discovered to be among the most potent inhibitors (IC50 values < or = 5 microM) of the bacterial two-component regulatory systems, KinA/SpoOF and NRII/NRI, reported to date. The Gram-positive antibacterial activity in selected strains is also presented.