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Oct 02, 2008
 |  BC Innovations  |  Cover Story

Truly Boronic

Researchers at Tufts University have shown that peptide boronic acid inhibitors of dipeptidyl peptidase-4 could provide effective, low-toxicity treatments for diabetes.1 The findings challenge the long-held assumption that boronic acids are too toxic for therapeutic use. Arisaph Pharmaceuticals Inc. has already in-licensed the related IP and has ARI-2243, a boronic acid inhibitor of dipeptidyl peptidase-4, in Phase I testing to treat diabetes.

Other companies contacted by SciBX said the findings make the case for taking another look at boronic acids as therapeutics, but they noted that the high potency makes selectivity a key issue, because that potency increases the likelihood of off-target effects at therapeutic doses.

Boronic acid redux

Dipeptidyl peptidase-4 (DPP-4) is expressed in many mammalian cells and tissues and plays a role in glucose metabolism. The serine protease degrades glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP), two gastrointestinal hormones secreted in response to the intake of food and involved in regulating insulin and glucose production.

Two non-boronic acid DPP-4 inhibitors are already approved for type 2 diabetes: Januvia sitagliptin, a selective DPP-4 inhibitor from Merck & Co. Inc., and Galvus vildagliptin, a nonselective DPP-4 inhibitor from Novartis AG. Two other non-boronic acid DPP-4 inhibitors are in registration for the indication: Onglyza saxagliptin from partners Bristol-Myers Squibb Co., AstraZeneca plc and Otsuka Pharmacetical Co. Ltd. and alogliptin from Takeda Pharmaceutical Co. Ltd.

However, dipeptide boronic acids were among the first-and are still among the most potent-inhibitors of DPP-4, according to William Bachovchin, leader of the Tufts team and CSO of Arisaph. In 1991, he and colleagues at Tufts reported the discovery of dipeptide boronic acids with binding affinities for DPP-4 that extended into the picomolar range.2 But he said that long-held-though unproven-assumptions about the intrinsic toxicity of boronic acids have largely precluded their commercial...

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