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  • Title: Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554.
    Author: Maezaki H, Banno Y, Miyamoto Y, Moritoh Y, Asakawa T, Kataoka O, Takeuchi K, Suzuki N, Ikedo K, Kosaka T, Sasaki M, Tsubotani S, Tani A, Funami M, Yamamoto Y, Tawada M, Aertgeerts K, Yano J, Oi S.
    Journal: Bioorg Med Chem; 2011 Aug 01; 19(15):4482-98. PubMed ID: 21741847.
    Abstract:
    Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC₅₀=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
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