Details

Autor(en) / Beteiligte

• Poplawski, Sarah E
• Lai, Jack H
• Sanford, David G
• Sudmeier, Wengen Wu, James L
• Bachovchin, William W

Titel

Pro-Soft Val-boroPro: A Strategy for Enhancing in Vivo Performance of Boronic Acid Inhibitors of Serine Proteases

Ist Teil von

• Journal of medicinal chemistry, 2011-04, Vol.54 (7), p.2022-2028

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.