RESUMO
A variety of trans-6-[2-(substituted-1-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones were prepared and, upon conversion to their 3,5-dihydroxy carboxylates, were found to have good inhibitory activity against the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-determining enzyme in cholesterogenesis. The most active compounds are 2,4,6- and 2,4,7-trichloro derivatives and would be expected to display about the same potency as the standard compactin upon resolution.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases , Naftalenos/síntese química , Piranos/síntese química , Fenômenos Químicos , Química , Físico-Química , Inibidores Enzimáticos/farmacologia , Humanos , Técnicas In Vitro , Naftalenos/metabolismo , Naftalenos/farmacologia , Piranos/metabolismo , Piranos/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 5-substituted thieno[2,3-b]- and thieno[3,2-b)- and thieno[3,2-b)thiophene-2-sulfonamides was prepared and evaluated for topical ocular hypotensive activity in glaucoma models. The 5-substituents were varied to maximize both inhibitory potency against carbonic anhydrase and water solubility. At the same time, these substituents were varied in order to obtain compounds with the appropriate pKa to minimize pigment binding in the iris. All of these variables were optimized in the best compound, 5-[[(methoxyethyl)[(methoxyethyl)ethyl] amino]methyl]thieno[2,3-b]thiophene-2-sulfonamide hydrochloride (55).
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Glaucoma/tratamento farmacológico , Hipotensão Ocular/tratamento farmacológico , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Animais , Inibidores da Anidrase Carbônica/síntese química , Técnicas In Vitro , Isomerismo , Modelos Moleculares , Coelhos , Sulfonamidas/síntese química , Tiofenos/síntese químicaRESUMO
A series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives have been prepared and tested for inhibition of HMG-CoA reductase in vitro. In general, unless a carboxylate anion can be formed and the hydroxy groups remain unsubstituted in an erythro relationship, inhibitory activity is greatly reduced. Furthermore, only one enantiomer of the ring-opened form of lactone 6a(+/-) possesses the activity displayed by the racemate. Insertion of a bridging unit other than ethyl or (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety (e.g., 2,4-dichlorophenyl) attenuates activity.
Assuntos
Glicóis/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases , Lactonas/farmacologia , Ácidos Pentanoicos/farmacologia , Valeratos/farmacologia , Glicóis/síntese química , Lactonas/síntese química , Ácidos Pentanoicos/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 7-(substituted aryl)-3,5-dihydroxy-6-heptenoic (heptanoic) acids and their lactone derivatives have been prepared and tested for inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vitro. A systematic exploration of the structure-activity relationships in this series led to the synthesis of (+)-trans-(E)-6-[2-[2,4-dichloro-6-[(4-fluorophenyl) methoxyl]phenyl]ethyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (66(+)), which has one-half of the inhibitory activity of compactin.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Ácidos Heptanoicos/farmacologia , Lactonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Novel 5-[(alkylamino)methyl]thieno[2,3-b]furan-2-sulfonamides were prepared and evaluated in vitro for inhibition of human carbonic anhydrase II (CA II) and ex vivo for their ability to inhibit Ca II in the albino rabbit eye after topical administration. Compound 11a was found to lower intraocular pressure (IOP) in both the alpha-CT ocular hypertensive albino rabbit and the normal albino rabbit, but was ineffective at lowering IOP in a hypertensive, pigmented monkey model. Since 11a was highly bound to ocular pigment, a series of less basic analogs was prepared. Examples in this series were both less extensively bound to ocular pigment and more active at reducing IOP in pigmented rabbits after topical dosing. Key examples displayed moderate reactivity toward glutathione.
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Pressão Intraocular/efeitos dos fármacos , Sulfonamidas/farmacologia , Administração Tópica , Animais , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Compostos de Dansil/metabolismo , Eritrócitos/enzimologia , Humanos , Coelhos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
A series of aminoalkyl-substituted pyridylureas has been prepared and evaluated as inhibitors of gastric acid secretion. N,N-Dimethyl-N'-[2-(diisopropylamino)ethyl]-N'-(4,6-dimethyl-2-pyridyl)urea (8g) was the most potent example of the class. Comparison of this compound with cimetidine showed it to be equipotent in dogs stimulated with gastrin tetrapeptide but approximately half as potent in dogs stimulated with histamine. Inhibition of secretion does not appear to result from antagonism of the histamine H2 receptor, since the compounds show only weak inhibition of the H2 receptor in vitro.
Assuntos
Ácido Gástrico/metabolismo , Piridinas/farmacologia , Ureia/análogos & derivados , Animais , Cimetidina/farmacologia , Cães , Feminino , Histamina/farmacologia , Tetragastrina/farmacologia , Ureia/farmacologiaRESUMO
The synthesis and pharmacology of 4, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of 4 to resting platelets is a diffusion-controlled process (kon = 3.3 x 10(6) M-1 s-1) and that 4 binds to dog and human platelets with comparable affinity (Kd = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 microg/kg [corrected], and an oral dose of 50-90 microg/kg [corrected] followed by low daily doses of 10 microg/kg [corrected] was sufficient to maintain approximately 80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 +/- 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.
Assuntos
Inibidores da Agregação Plaquetária/síntese química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Sulfonamidas/síntese química , Tiofenos/síntese química , Administração Oral , Animais , Ligação Competitiva , Tempo de Sangramento , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Técnicas In Vitro , Injeções Intravenosas , Masculino , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ensaio Radioligante , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Compound affinity for activated and resting GPIIb/IIIa receptors may differ, and comparison of those differences determines selectivity. Structural features that influence selectivity are discussed.