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Yoshihiro Banno,
Yasufumi Miyamoto,
Mitsuru Sasaki,
Satoru Oi,
Tomoko Asakawa,
Osamu Kataoka,
Koji Takeuchi,
Nobuhiro Suzuki,
Koji Ikedo,
Takuo Kosaka,
Shigetoshi Tsubotani,
Akiyoshi Tani,
Miyuki Funami,
Michiko Tawada,
Yoshio Yamamoto,
Kathleen Aertgeerts,
Jason Yano,
Hironobu Maezaki
[show abstract]
[hide abstract]
ABSTRACT: The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors.
Bioorganic & medicinal chemistry 08/2011; 19(16):4953-70. · 2.82 Impact Factor
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Hironobu Maezaki, Yoshihiro Banno,
Yasufumi Miyamoto,
Yusuke Moritoh,
Yuusuke Moritou,
Tomoko Asakawa,
Osamu Kataoka,
Koji Takeuchi,
Nobuhiro Suzuki,
Koji Ikedo,
Takuo Kosaka,
Masako Sasaki,
Shigetoshi Tsubotani,
Akiyoshi Tani,
Miyuki Funami,
Yoshio Yamamoto,
Michiko Tawada,
Kathleen Aertgeerts,
Jason Yano,
Satoru Oi
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry 08/2011; 19(15):4482-98. · 2.82 Impact Factor
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Yasufumi Miyamoto, Yoshihiro Banno,
Tohru Yamashita,
Tatsuhiko Fujimoto,
Satoru Oi,
Yusuke Moritoh,
Tomoko Asakawa,
Osamu Kataoka,
Hiroaki Yashiro,
Koji Takeuchi, [......],
Takuo Kosaka,
Shigetoshi Tsubotani,
Akiyoshi Tani,
Masako Sasaki,
Miyuki Funami,
Michiko Amano,
Yoshio Yamamoto,
Kathleen Aertgeerts,
Jason Yano,
Hironobu Maezaki
[show abstract]
[hide abstract]
ABSTRACT: Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.
Journal of Medicinal Chemistry 01/2011; 54(3):831-50. · 4.80 Impact Factor
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Yasufumi Miyamoto, Yoshihiro Banno,
Tohru Yamashita,
Tatsuhiko Fujimoto,
Satoru Oi,
Yusuke Moritoh,
Tomoko Asakawa,
Osamu Kataoka,
Koji Takeuchi,
Nobuhiro Suzuki,
Koji Ikedo,
Takuo Kosaka,
Shigetoshi Tsubotani,
Akiyoshi Tani,
Miyuki Funami,
Michiko Amano,
Yoshio Yamamoto,
Kathleen Aertgeerts,
Jason Yano,
Hironobu Maezaki
[show abstract]
[hide abstract]
ABSTRACT: We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.
Bioorganic & medicinal chemistry 01/2011; 19(1):172-85. · 2.82 Impact Factor
