Pro-soft Val-boroPro: a strategy for enhancing in vivo performance of boronic acid inhibitors of serine proteases.
J Med Chem
; 54(7): 2022-8, 2011 Apr 14.
Article
em En
| MEDLINE
| ID: mdl-21388136
Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency >100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to 1. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Borônicos
/
Pró-Fármacos
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Inibidores de Serina Proteinase
/
Dipeptídeos
/
Inibidores da Dipeptidil Peptidase IV
/
Serina Proteases
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article