RESUMO
PURPOSE: The purpose of this study was to evaluate the efficacy of an aqueous calcineurin inhibitor, SCY-641, in the treatment of naturally occurring canine immune-mediated keratoconjunctivitis sicca (KCS). METHODS: A randomized, double-masked, placebo-controlled clinical study of 56-day duration was performed in dogs with naturally occurring immune-mediated KCS assigned to treatment with either topical twice-daily aqueous calcineurin inhibitor solution (SCY-641) or artificial tears (placebo) by the study administrator. Clinical examination and Schirmer tear tests (STT) were performed prior to therapy and at days 7, 14, 28, and 56 after initiation of treatment. RESULTS: Twenty dogs were enrolled in the study with ten receiving placebo and 10 receiving SCY-641 in one or both eyes. No adverse effects were noted with any treatment. There were no significant differences in mean STT values in dogs in group either at day 0 (prior to therapy) or after 7 days of treatment. At 14, 28, and 56 days after initiation of treatment, mean STT and increase in STT over baseline in dogs treated with SCY-641 were significantly higher than in dogs treated with placebo (P < 0.04). CONCLUSIONS: SCY-641 was well tolerated by dogs with naturally occurring KCS, and by 14 days after initiating therapy, dogs treated with SCY-641 had significantly higher STT than placebo-treated dogs. These preliminary results indicate that topical SCY-641, in a stable clear aqueous solution, is efficacious in a spontaneous model of KCS and warrants further evaluation as a treatment of immune-mediated KCS.
Assuntos
Inibidores de Calcineurina , Ciclosporinas/farmacologia , Doenças do Cão/tratamento farmacológico , Ceratoconjuntivite Seca/veterinária , Administração Tópica , Animais , Cães , Método Duplo-Cego , Ceratoconjuntivite Seca/tratamento farmacológico , Projetos PilotoRESUMO
Orally bioavailable inhibitors of ß-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.
Assuntos
Antifúngicos/síntese química , Inibidores Enzimáticos/síntese química , Glucosiltransferases/antagonistas & inibidores , Glicosídeos/química , Triterpenos/química , Administração Oral , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Glucosiltransferases/metabolismo , Glicosídeos/síntese química , Glicosídeos/farmacocinética , Meia-Vida , Camundongos , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/farmacocinéticaRESUMO
A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3beta.
Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Modelos Moleculares , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Piridinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Área Sob a Curva , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
[reaction: see text] A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved either via a regioselective [3 + 2] cycloaddition of N-aminopyridines with alkynes or by thermal cyclization of disubstituted azirines. Subsequent palladium-catalyzed introduction of pyridines or de novo synthesis of pyrimidines affords inhibitors of p38 kinase.