RESUMO
A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent and highly selective (1000-9000-fold) inhibitors of the human COX-2. 3-Pyridyl derived COX-2 selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED(50) = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED(50) = 0.25 mg/kg) models of inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78) demonstrated excellent oral activity in every efficacy model evaluated. Several orally active diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and antiinflammatory properties of a series of diarylimidazoles are discussed.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Inibidores de Ciclo-Oxigenase/síntese química , Imidazóis/síntese química , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Artrite Experimental/tratamento farmacológico , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/toxicidade , Cães , Edema/tratamento farmacológico , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Hiperalgesia/tratamento farmacológico , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/toxicidade , Intestinos/efeitos dos fármacos , Intestinos/patologia , Proteínas de Membrana , Camundongos , Nitrilas/síntese química , Piridinas/química , Ratos , Estômago/efeitos dos fármacos , Estômago/patologia , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaAssuntos
Anti-Inflamatórios não Esteroides/síntese química , Inibidores Enzimáticos/síntese química , Isoenzimas/farmacologia , Isoxazóis/síntese química , Prostaglandina-Endoperóxido Sintases/farmacologia , Sulfonamidas/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Ciclo-Oxigenase 2 , Edema/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/sangue , Isoxazóis/farmacologia , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/sangue , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Sulfonamidas/farmacologiaRESUMO
Series of 1,2-diarylimidazoles has been synthesized and found to contain highly potent and selective inhibitors of the human COX-2 enzyme. The paper describes a short synthesis of the target 1,2-diarylimidazoles starting with aryl nitriles. Different portions of the diarylimidazole (I) were modified to establish SAR. Systematic variations of the substituents in the aryl ring B have yielded very potent (IC50 = 10-100 nm) and selective (1000-12500) inhibitors of the COX-2 enzyme. The study on the influence of substituents in the imidazole ring established that a CF3 group at position 4 gives the optimum oral activity. A number of the diarylimidazoles showed excellent inhibition in the adjuvant induced arthritis model (e.g., ED50 = 0.02 mpk for 22 and 34). The diarylimidazoles are also potent inhibitors of carrageenan-induced edema (ED50 = 9-30 mpk) and hyperalgesia (ED50 = 11-40 mpk). Several orally active diarylimidazoles show no GI toxicity in the rat and mouse up to 200 mpk.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Inibidores de Ciclo-Oxigenase/síntese química , Imidazóis/síntese química , Isoenzimas , Prostaglandina-Endoperóxido Sintases , Sulfonamidas/síntese química , Sulfonas/síntese química , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Carragenina , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Gastroenteropatias/induzido quimicamente , Humanos , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Proteínas de Membrana , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sulfonas/farmacologia , Sulfonas/uso terapêuticoRESUMO
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
Assuntos
Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Carragenina/farmacologia , Celecoxib , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacocinética , Hiperalgesia/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Masculino , Proteínas de Membrana , Estrutura Molecular , Osteoartrite/tratamento farmacológico , Pirazóis , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs 17 and 21 were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs 16 and 20, respectively, albeit with some decrease in COX-2 selectivity. Structure-activity relationship studies have determined that incorporation of two fluorine atoms in the central phenyl group, as in 20 and 21, is extremely advantageous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several noticeable examples in the 1,2-diaryl-4,5-difluorobenzenesulfonamide series are 21a-c,k,l,n (COX-2, IC50 = 0.002-0.004 microM), in which all have in vitro COX-1/COX-2 selectivity > 1000. In addition, sulfonamides 21a,b,d,g,j,m,n,q were shown to have greatly enhanced oral activity with more than 90% inhibition of prostaglandin E2 production in the air pouch model of inflammation. Furthermore, sulfonamide 21b was found to be very active in the rat adjuvant-induced arthritis model (ED50 = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED50 = 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200 mg/kg.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Compostos de Terfenil/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/uso terapêutico , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Ratos , Compostos de Terfenil/administração & dosagem , Compostos de Terfenil/química , Compostos de Terfenil/uso terapêuticoRESUMO
A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.
Assuntos
Anti-Inflamatórios não Esteroides/química , Inibidores de Ciclo-Oxigenase/síntese química , Compostos de Espiro/síntese química , Sulfonamidas/síntese química , Sulfonas/síntese química , Analgésicos/síntese química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Carragenina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacocinética , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Humanos , Intestinos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estômago/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfonas/química , Sulfonas/farmacocinética , Sulfonas/farmacologiaRESUMO
We have recently been involved in the development of a method for assaying the active component in a controlled-release drug formulation, which is composed of a drug substance covalently bonded to polymer matrix. The drug substance in the formulation is the active enantiomer of misoprostol, a synthetic analog of natural prostaglandins and the active ingredient in Cytotec. Our method development consisted of a systematic evaluation of dynamic, off-line supercritical fluid extraction (SFE) as sample preparation for the formulation assay. Extracts were analyzed with normal phase and reversed-phase HPLC methods. The reversed-phase system utilized postcolumn reaction to provide selective detection of the extracted prostaglandin sample components. Several SFE parameters were investigated to optimize the recovery of the drug substance from the formulation, including sample quantity, extraction cell volume, extraction duration, supercritical carbon dioxide modifier, temperature, pressure, and collection solvent. The SFE experiments were completed with a commercially available multicell extractor. Preliminary validation studies utilized a formulation made with radiolabeled drug to determine the recovery achieved under the optimized SFE conditions and assessed the precision of replicate determinations. Analysis was completed under the optimized conditions to quantitate levels of the active component and related compounds in lots of the experimental polymeric formulation and to determine the total weight per cent extracted.
Assuntos
Preparações de Ação Retardada/análise , Dióxido de Carbono/química , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Indicadores e Reagentes , Marcação por Isótopo , Misoprostol/análise , Polímeros , Solventes , Espectrofotometria UltravioletaRESUMO
Prostaglandins (PGs) in the E-series exhibit potent gastric antisecretory activity, but can also cause diarrhea, which is mediated via PGE receptors. SC-46275, an omega-chain cyclopentenyl analog of the E-type PG enisoprost, was evaluated with other E-PGs for PGE receptor binding activity in gastric and intestinal tissues. SC-46275, enisoprost, misoprostol and PGE1 were first evaluated in enriched canine gastric parietal cells with [3H]misoprostol free acid binding and subsequently with [3H]PGE1 binding in canine intestinal tissues where misoprostol free acid had weak receptor binding activity. The receptor binding potency of SC-46275 (IC50, 0.013 mM) in enriched canine parietal cell preparations was found to be much greater than misoprostol and enisoprost (IC50, 10 and 8 nM), whereas PGE1 had the least potency (IC50, 37 nM). Similar relative potencies for these PGs were also obtained in the inhibition of histamine-stimulated acid secretion in enriched parietal cell preparations. In small intestinal mucosal and muscle membranes, the receptor binding potency of SC-46275 (IC50, 13 and 20 microM) was much less than misoprostol or enisoprost (IC50, 0.39-1.2 microM) and substantially less than PGE1 (IC50, 0.017 and 0.066 microM). This weak binding activity of SC-46275 in intestinal tissues is consistent with its reported weak diarrheagenic activity in the rat. These results suggest that SC-46275 binds preferentially to gastric vs. intestinal PGE receptors and is specific for the EP3 receptors.
Assuntos
Alprostadil/análogos & derivados , Antiulcerosos/metabolismo , Intestino Delgado/ultraestrutura , Receptores de Prostaglandina E/metabolismo , Estômago/ultraestrutura , Alprostadil/metabolismo , Alprostadil/farmacologia , Animais , Antiulcerosos/farmacologia , Células Cultivadas , Cães , Feminino , Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Masculino , Misoprostol/metabolismo , Misoprostol/farmacologia , Músculo Liso/metabolismo , Músculo Liso/ultraestrutura , Ensaio Radioligante , Estômago/efeitos dos fármacos , TrítioRESUMO
To determine the mode of protective effects of misoprostol against the chronic gastrointestinal ulceration from the NSAID, diclofenac, studies were undertaken in domestic pigs, a model of human gastrointestinal ulceration, to determine (1) the effects of repeated daily dosing for 10 days of diclofenac 5 mg/kg/day twice a day (as Voltaren tablets) on the gastrointestinal morphology, 59fe-red blood loss, mucosal myeloperoxidase (MPO) activity (as an indicator of leukocyte infiltration), and mucosal leukotrienes (LTS); and (2) the mucosal protective effects of 10-40 micrograms/kg/day misoprostol twice a day (as Cytotec tablets) given with diclofenac 5 mg/kg/day twice a day compared with diclofenac 5 mg/kg/day alone and aspirin 150 mg/kg/twice a day (USP tablets) as a standard. These effects were compared with the dose range for potential diarrheagenic effects of misoprostol (determined by fecal analysis of NA+, K+, CL-, CA2+, H2O, and phenol red transit) given alone or with diclofenac to determine if this could be discriminated from antiulcer effects of misoprostol. Plasma and gastric mucosal concentrations of the drugs were determined to establish if misoprostol affects diclofenac absorption/elimination, and vice versa. The results showed that: (1) diclofenac produced gastric mucosal damage without any prior or concurrent bleeding from the gastrointestinal tract, although aspirin significantly increased blood loss; (2) misoprostol produced a dose-related reduction in diclofenac-induced mucosal damage of the upper gastrointestinal tract; (3) no significant increase in mucosal MPO occurred with diclofenac despite mucosal damage being evident, (4) mucosal LTS were unaffected by the drug treatments; (5) plasma, gastric and intestinal concentrations of diclofenac were not affected by misoprostol, while conversely plasma misoprostol concentrations were not influenced by the diclofenac treatment; (6) no significant effects on fecal water, electrolyte, or phenol red transit times were observed with an of the drug-treatments; and (7) mild diarrhea observed as "loose bowel motions" was only observed in most pigs receiving the misoprostol treatments during fasting on days 9-10. Thus, misoprostol protects against chronic lesions/ulcers in the upper gastrointestinal tract from diclofenac without: (1) signs of diarrhea becoming evident (the latter occurring when there is reduced food intake), (2) generalized leukocyte infiltration or effects on mucosal LTs, or (3) any reduction in bioavailability of diclofenac.
Assuntos
Diarreia/induzido quimicamente , Diclofenaco/administração & dosagem , Sistema Digestório/efeitos dos fármacos , Leucócitos/citologia , Leucotrienos/metabolismo , Misoprostol/administração & dosagem , Animais , Disponibilidade Biológica , Diarreia/prevenção & controle , Diclofenaco/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Peroxidase/metabolismo , SuínosRESUMO
SC-30249 is the active isomer of misoprostol responsible for its mucosal protective effects against nonsteroidal anti-inflammatory drugs (NSAIDS). Linkage of SC-30249 to a polybutadiene polymer results in a delivery system (SC-55307) that releases the active component only under the acidic conditions of the stomach. This approach could be used to minimize side effects and systemic availability of synthetic prostaglandins. These studies were done to determine whether uterotonic activity could be recorded after treatment with SC-55307. Female beagles were implanted with uterine strain gauge force transducers, allowed 10 days for recovery and treated with estrogen to sensitize the uterus to the actions of prostaglandins. Base-line responses were determined with SC-30249, i.v., and then a randomized series of four treatments were given: SC-30249, IG, 10 micrograms/kg; SC-55307, IG, equivalent to 30 and 100 micrograms/kg of SC-30249; and a blank polymer control. HCI was given IG to provide an acid environment in the stomach, uterine responses were obtained for up to 4 h and plasma concentrations of SC-30249 free acid was determined. No uterotonic effect was seen after a low dose of SC-55307, whereas the high dose caused a brief but statistically significant increase equal to 8.8% and 17.8% of the responses to SC-30249, i.v. and IG, respectively. Peak plasma levels of SC-30249 free acid were 176.4 +/- 17.4 and 59.5 +/- 10.6 pg/ml after SC-30249, i.v. and IG, respectively, but were only 3.9 +/- 1.7 and 15.5 +/- 6.6 pg/ml after low and high doses of SC-55307, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Misoprostol/farmacologia , Miométrio/efeitos dos fármacos , Animais , Disponibilidade Biológica , Butadienos , Cães , Portadores de Fármacos , Feminino , Mucosa Gástrica/efeitos dos fármacos , Isomerismo , Misoprostol/administração & dosagem , Misoprostol/farmacocinética , Contração Muscular/efeitos dos fármacos , Miométrio/fisiologia , PolímerosAssuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Ciclopentanos/farmacologia , Administração Oral , Animais , Artrite Experimental/tratamento farmacológico , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/síntese química , Ciclopentanos/administração & dosagem , Ciclopentanos/síntese química , Camundongos , RatosRESUMO
SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.
Assuntos
Butadienos , Enteropatias/induzido quimicamente , Metilcelulose/análogos & derivados , Misoprostol , Misoprostol/administração & dosagem , Polímeros , Gastropatias/induzido quimicamente , Animais , Antiácidos/farmacologia , Aspirina/toxicidade , Disponibilidade Biológica , Depressão Química , Diarreia/induzido quimicamente , Cães , Portadores de Fármacos , Etanol/toxicidade , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Derivados da Hipromelose , Indometacina/toxicidade , Enteropatias/prevenção & controle , Masculino , Misoprostol/farmacocinética , Misoprostol/toxicidade , Ratos , Ratos Endogâmicos , Gastropatias/prevenção & controleRESUMO
The application of functionalized polymers to site-directed delivery of the antiulcer prostaglandin, misoprostol, is described. By use of homogeneous catalysis, the simple polymer, polybutadiene, was modified to incorporate the specialized requirements for controlled delivery of misoprostol to the stomach. An acid labile silyl ether bond to the C-11 hydroxyl of misoprostol was installed as the primary rate determining step for drug release, and a series of analogs, in which the steric hindrance about the silicon atom was varied, was prepared and evaluated for in vitro release rates, efficacy against indomethacin induced gastric damage and diarrheagenic activity. The diisopropylsilyl analog, the slowest releasing system studied, showed efficacy equal to misoprostol against indomethacin-induced gastric damage and no diarrhea at the highest dose tested.
Assuntos
Butadienos/farmacologia , Misoprostol/administração & dosagem , Polímeros/farmacologia , Estômago/efeitos dos fármacos , Animais , Preparações de Ação Retardada , Diarreia/induzido quimicamente , Sistemas de Liberação de Medicamentos , Elastômeros , Concentração de Íons de Hidrogênio , Masculino , Misoprostol/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Prostaglandin E (PGE) receptors in canine small intestinal mucosal and muscle membrane preparations were labeled with [3H] PGE1. Saturable, high affinity binding of [3H] PGE1 was observed in both preparations. The density of binding sites (fmol/mg protein) was 39 for mucosal membranes and 60 for muscle membranes, with corresponding dissociation constants of 10.6 nM and 5.8 nM, respectively. [3H] PGE1 binding sites in both preparations showed stereospecificity and high affinity for natural PGE1 and PGE2, but not for I or F-type PGs. Synthetic PGEs such as misoprostol and enisoprost had lower affinity than PGE1 or PGE2. Several analogs of enisoprost bound weakly to the binding sites. A highly significant correlation (C.C. = 0.9) was demonstrated between mucosal and muscle binding potency for a series of enisoprost analogs. There was also a significant positive correlation between the receptor binding potency and rat diarrheagenic activity for these analogs. These results indicate that PGE receptors in canine intestinal mucosa and muscle can be directly studied with [3H] PGE1 binding. The mucosal and muscle PGE receptors may have similar ligand binding specificity. We speculate that these receptors are likely to be associated with the diarrheagenic activity of PGEs.
Assuntos
Alprostadil/metabolismo , Intestino Delgado/metabolismo , Receptores de Prostaglandina/metabolismo , Alprostadil/análogos & derivados , Alprostadil/farmacologia , Animais , Antiulcerosos/farmacologia , Diarreia/induzido quimicamente , Cães , Intestino Delgado/efeitos dos fármacos , Masculino , Misoprostol/farmacologia , Estrutura Molecular , Ratos , Receptores de Prostaglandina/efeitos dos fármacos , Receptores de Prostaglandina E , Sensibilidade e Especificidade , TrítioRESUMO
A series of acyclic omega chain conjugated diene analogues of enisoprost were synthesized and evaluated for gastric antisecretory and diarrheagenic activities in comparison to enisoprost and a previously identified cyclic dienyl analogue. Several novel approaches to the cuprate reagents involved in the synthesis of the series are described. From this SAR study, it appears that both the conjugated diene and the overall space filling characteristics of the omega chain are important components to the pharmacological profiles and selectivity of these compounds and that a cyclic structure is not required.
Assuntos
Alprostadil/análogos & derivados , Antiulcerosos/síntese química , Alprostadil/química , Alprostadil/farmacologia , Animais , Antiulcerosos/farmacologia , Diarreia/induzido quimicamente , Cães , Feminino , Ácido Gástrico/metabolismo , Suco Gástrico/efeitos dos fármacos , Masculino , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The synthetic prostaglandin, SC-46275, an omega chain cyclopentenyl analog of enisoprost, was studied to determine its gastric antisecretory potency and duration of action in meal-stimulated innervated (Pavlov) pouch dogs and its p.o. bioavailability in unoperated fasted dogs. SC-46275 exhibited potent antisecretory activity when administered directly into the gastric pouch, the ED50 being 0.01 micrograms/kg. It had a long duration of antisecretory action; significant (P less than or equal to .05) inhibition of total acid output was observed 16 hr after intrapouch administration of 0.03 micrograms/kg. At this dose p.o., neither SC-46275 nor its free acid metabolite was detected in plasma. These data indicate that SC-46275 has novel properties: it is a potent, long-acting gastric antisecretory agent which is not readily available systemically after p.o. administration. Thus, potential systemic side effects are expected to be absent or minimized at doses of SC-46275 which inhibit gastric acid secretion, and therefore it might be useful in peptic ulcer disease.
Assuntos
Alprostadil/análogos & derivados , Antiulcerosos/farmacocinética , Mucosa Gástrica/efeitos dos fármacos , Administração Oral , Alprostadil/farmacocinética , Alprostadil/farmacologia , Animais , Antiulcerosos/farmacologia , Disponibilidade Biológica , Cães , Relação Dose-Resposta a Droga , Feminino , Mucosa Gástrica/metabolismo , TrítioRESUMO
A series of delta 17 unsaturated cycloalkyl and cycloalkenyl analogues of enisoprost was synthesized to investigate the effects of omega chain unsaturation on gastric antisecretory activity and diarrheogenic side effects. Of these, the 17E, 18-cyclopentenyl analogue 5d displayed potent gastric antisecretory activity in dogs but very weak diarrheogenic properties in rats and is the most selective prostaglandin compound discovered in these laboratories. Structurally, 5d contains both a conjugated diene and tertiary allylic alcohol in the omega chain, and these chemical features impart some interesting oxidative and acid-catalyzed epimerization and allylic rearrangement reactivities, respectively.
Assuntos
Alprostadil/análogos & derivados , Antiulcerosos/síntese química , Alprostadil/síntese química , Alprostadil/química , Alprostadil/farmacologia , Animais , Antiulcerosos/química , Diarreia/induzido quimicamente , Cães , Desenho de Fármacos , Suco Gástrico/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , Ratos , Taxa Secretória/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
By use of standard cuprate methodology, a series of 18-cycloalkyl analogues of enisoprost was prepared in an effort to impede omega chain metabolism and prolong duration of gastric antisecretory activity. An initial product of omega chain oxidation, the C-20 hydroxy analogue, was also synthesized for pharmacological comparison. The cyclopropyl, cyclobutyl, and cyclopentyl analogues were approximately one-fourth as potent as enisoprost in inhibiting gastric acid secretion, while the cyclohexyl and cycloheptyl analogues showed very weak activity, and the 20-hydroxy compound was inactive at a dose 100 times the ED50 of enisoprost. The cyclobutyl compound had a longer duration of antisecretory action than enisoprost and the other cycloalkyl analogues. The cycloalkyl analogues unexpectedly possessed low diarrheogenic activity in rats.
Assuntos
Alprostadil/análogos & derivados , Antiulcerosos/síntese química , Alprostadil/síntese química , Alprostadil/farmacologia , Animais , Antiulcerosos/farmacologia , Diarreia/induzido quimicamente , Cães , Feminino , Ácido Gástrico/metabolismo , Masculino , Ratos , Relação Estrutura-AtividadeRESUMO
Metoclopramide has gained acceptance as an effective drug for the control of nausea and vomiting in cancer patients receiving cisplatin chemotherapy. In addition to its emetogenic side effects, cisplatin is known to be nephrotoxic. This animal study was undertaken to determine if the severity of cisplatin-induced nephrotoxicity is altered by the coadministration of metoclopramide. Female F-344 rats received subcutaneous saline or metoclopramide 30 min before and 120 min after intravenous administration of saline or cisplatin. Animals were sacrificed on the 5th day following treatment. Decreases in body weight, elevations in serum urea nitrogen and histopathological changes were of similar magnitude in all cisplatin treated groups regardless of concomitant metoclopramide administration. Saline dosed control animals did not exhibit these changes. It is concluded that the coadministration of metoclopramide did not significantly alter the nephrotoxic effects of cisplatin in this experiment.
Assuntos
Cisplatino/toxicidade , Nefropatias/induzido quimicamente , Metoclopramida/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Cisplatino/antagonistas & inibidores , Feminino , Rim/patologia , Nefropatias/patologia , Ratos , Ratos Endogâmicos F344RESUMO
Mitoxantrone (DHAQ) was compared to doxorubicin for myocardial effects in the mouse and the guinea pig. Histologically, DHAQ induced a high incidence of focal myocardial damage in mice, similar to that observed with doxorubicin. Functionally, like doxorubicin, DHAQ significantly reduced the rate of contraction and histamine responsiveness of guinea pig right atria in vitro. Additionally, long-term ip administration of either DHAQ or doxorubicin reduced the atrial response to histamine in vitro. These data suggest that DHAQ may have a spectrum of myocardial activity similar to that of doxorubicin.