RESUMO
Daclatasvir is a novel hepatitis C virus NS5A inhibitor developed by Bristol-Myers Squibb and marketed as Daklinza®. The need to support the development of daclatasvir required the synthesis of carbon-14 labeled material for use in human absorption, distribution, metabolism, and excretion studies. A total of 7.53 mCi of [(14) C]-daclatasvir was synthesized in eight steps from commercially available [(14) C]-copper cyanide. The radiochemical purity was 99.6%, and specific activity was 3.86 µCi/mg. To support a human absolute bioavailability study, 5.56 g of [(13) C2 , (15) N4 ]-daclatasvir was synthesized in four steps.
Assuntos
Imidazóis/síntese química , Imidazóis/farmacocinética , Disponibilidade Biológica , Carbamatos , Técnicas de Química Sintética , Humanos , Imidazóis/química , Imidazóis/metabolismo , Marcação por Isótopo , Pirrolidinas , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Teprotida/síntese química , Teprotida/química , Teprotida/metabolismo , Teprotida/farmacocinética , Valina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.
Assuntos
Inibidores de Fosfodiesterase/química , Pirazóis/química , Piridazinas/química , Piridinas/química , Teprotida , Sítios de Ligação , Ativação Enzimática/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Piridinas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Teprotida/síntese química , Teprotida/química , Teprotida/farmacologiaRESUMO
Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.
Assuntos
Neoplasias Hematológicas , Neoplasias , Teprotida , alfa-Manosidase/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Teprotida/síntese química , Teprotida/química , Teprotida/farmacologiaAssuntos
Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/síntese química , Captopril/farmacologia , Teprotida/síntese química , Teprotida/farmacologia , Desenho de Fármacos , Humanos , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismoRESUMO
Affinity labeled analogues and partial sequences of the bradykinin potentiating nonapeptide BPP9 alpha inhibit the BPP9 alpha induced potentiation of the bradykinin action on the isolated guinea pig ileum. The labeled nonapeptides are more active than the labeled partial sequences. The inhibition of the potentiating action of BPP9 alpha demonstrates, that the influence on bradykinin action is not only a result of the inhibition of peptidyl dipeptide hydrolase.
Assuntos
Bradicinina/farmacologia , Oligopeptídeos/síntese química , Teprotida/síntese química , Marcadores de Afinidade/síntese química , Animais , Fenômenos Químicos , Química , Sinergismo Farmacológico , Cobaias , Técnicas In Vitro , Cinética , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Inibidores de Proteases , Teprotida/farmacologiaRESUMO
The synthesis of 5 analogues of the effective inhibitor of peptidyl dipeptidase, teprotide, has been carried out. The inhibitory and bradykinin-potentiating activity of these compounds has been assayed. N-Terminal pyroglutamic acid and positive charge of arginine in position 4 were found to be essential for biological activity of the inhibitor.