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1.
Bioorg Med Chem Lett ; 24(8): 1875-9, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24684843

RESUMO

A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dosing. Modifications of the 2-(piperazin-1-yl)pyrazine derivatives produced compounds with improved solubility and physicochemical properties. Modifications of the 6-pyrazine substituent led to improvements in in vitro potency. Compound 9 had the best in vitro and in vivo potency of EC50=260 nM with a 30% reduction of IOP in a non-human primate model at a dose of 0.33%.


Assuntos
Glaucoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/síntese química , Pirazinas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Piridinas/uso terapêutico
2.
J Ocul Pharmacol Ther ; 30(1): 21-34, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24236827

RESUMO

PURPOSE: To localize mRNA and protein of bradykinin (BK) receptors, BK precursor polypeptide (kininogen) mRNA, and to study functional biochemical pharmacology of the signal transduction processes mediated by B2-receptors in isolated human trabecular meshwork (h-TM) cells. Intraocular pressure (IOP) lowering effects of 2 kinins were also investigated. METHODS: Previously documented procedures were utilized throughout these studies. RESULTS: Kinninogen mRNA was most abundant in TM, ciliary body (CB), and optic nerve head and appeared elevated in glaucomatous h-TM tissue. High levels of B2-receptor mRNA were found in the sclera, iris, TM, and CB. B2-receptor subtype protein was localized in cells of the monkey and h-TM, and the treatment of isolated h-TM cells with transforming growth factor-ß2 (5 ng/mL) caused significant (P<0.04) downregulation of B2-receptor mRNA. In isolated primary h-TM cells, BK (EC50=0.8±0.2 nM; n=19) and Met-Lys-BK (EC50=6.5±1.5 nM) mobilized intracellular Ca(2+) and induced the release of prostaglandins (PGs) that was blocked by 2 B2-receptor antagonists [HOE-140; (S)-WIN-64338]. The cyclooxygenase inhibitor, bromfenac, abolished BK-induced PGs production. BK concentration dependently increased cell impedance, and it significantly (P<0.05) decreased h-TM cell volume in vitro. Intravitreal (ivt) administration of BK (50 µg), but not a B1-agonist (Sar-[D-Phe(9)]-Des-Arg(9)-BK; also at 50 µg), efficaciously lowered IOP (22.9% to 37% from baseline) of Dutch-Belted rabbits that naturally have high IOPs (27-28 mmHg). CONCLUSIONS: BK activates multiple signal transduction pathways in h-TM cells via B2-receptors that also mediate IOP reduction as observed in rabbits following ivt administration of BK. These ocular hypotensive effects of BK may be physiologically important and suggest a novel therapeutic potential of BK-related B2-agonists.


Assuntos
Pressão Intraocular/fisiologia , Cininogênios/metabolismo , RNA Mensageiro/metabolismo , Receptores da Bradicinina/metabolismo , Idoso , Animais , Benzofenonas/farmacologia , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/metabolismo , Bradicinina/farmacologia , Antagonistas de Receptor B2 da Bradicinina , Bromobenzenos/farmacologia , Feminino , Humanos , Imuno-Histoquímica , Pressão Intraocular/efeitos dos fármacos , Cininogênios/genética , Macaca fascicularis , Masculino , Naftalenos/farmacologia , Compostos Organofosforados/farmacologia , Prostaglandinas/metabolismo , Coelhos , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Transdução de Sinais/fisiologia , Malha Trabecular/citologia , Malha Trabecular/metabolismo
3.
Planta Med ; 73(6): 591-6, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17486535

RESUMO

The Red Sea sponge Callyspongia (= Siphonochalina) siphonella is a rich source of sipholane triterpenoids. Biocatalysis of the major sipholanes, sipholenol A (1) and sipholenone A (2), respectively, by Mucor ramannianus ATCC 9628 and Cunninghamella elegans ATCC 7929 afforded four new metabolites 3 - 6 along with sipholenol G and 28-hydroxysipholenol A. Major sipholanes along with their biocatalytic products were investigated for their antiproliferative activity against the highly malignant +SA mouse mammary epithelial cell line. Sipholenone A (2) was the most active sipholane inhibiting +SA cell proliferation with an IC(50) value of 20 - 30 microM. Sipholenone A, also, showed cytotoxicity against MCF-7 at a dose of 0.9 microM and antiangiogenic activity in the CAM (chorio-allantoic membrane) assay. This is the first report on anticancer activity of these triterpenoids.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Callyspongia , Fitoterapia , Extratos Vegetais/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Embrião de Galinha/efeitos dos fármacos , Galinhas , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Triterpenos/administração & dosagem , Triterpenos/farmacologia , Triterpenos/uso terapêutico
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