Ikedo K

References (5)

Title : Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554 - Maezaki_2017_Bioorg.Med.Chem.Lett_27_3565
Author(s) : Maezaki H , Tawada M , Yamashita T , Banno Y , Miyamoto Y , Yamamoto Y , Ikedo K , Kosaka T , Tsubotani S , Tani A , Asakawa T , Suzuki N , Oi S
Ref : Bioorganic & Medicinal Chemistry Lett , 27 :3565 , 2017
Abstract : We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1' pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or nanomolar inhibitors of human DPP-4. Docking studies suggested that a hydrophobic interaction with Tyr547 as well as the salt bridge interaction is important for the extremely high potency. The design strategy would be useful to explore a novel design for DPP-4 inhibitors having a distinct structure with a unique binding mode.
ESTHER : Maezaki_2017_Bioorg.Med.Chem.Lett_27_3565
PubMedSearch : Maezaki_2017_Bioorg.Med.Chem.Lett_27_3565
PubMedID: 28579121

Title : Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: a new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554 - Banno_2011_Bioorg.Med.Chem_19_4953
Author(s) : Banno Y , Miyamoto Y , Sasaki M , Oi S , Asakawa T , Kataoka O , Takeuchi K , Suzuki N , Ikedo K , Kosaka T , Tsubotani S , Tani A , Funami M , Tawada M , Yamamoto Y , Aertgeerts K , Yano J , Maezaki H
Ref : Bioorganic & Medicinal Chemistry , 19 :4953 , 2011
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)o xy]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.
ESTHER : Banno_2011_Bioorg.Med.Chem_19_4953
PubMedSearch : Banno_2011_Bioorg.Med.Chem_19_4953
PubMedID: 21764322
Gene_locus related to this paper: human-DPP4

Title : Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554 - Maezaki_2011_Bioorg.Med.Chem_19_4482
Author(s) : 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
Ref : Bioorganic & Medicinal Chemistry , 19 :4482 , 2011
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 (IC(5)(0)=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.
ESTHER : Maezaki_2011_Bioorg.Med.Chem_19_4482
PubMedSearch : Maezaki_2011_Bioorg.Med.Chem_19_4482
PubMedID: 21741847
Gene_locus related to this paper: human-DPP4

Title : Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125 - Miyamoto_2011_Bioorg.Med.Chem_19_172
Author(s) : Miyamoto Y , Banno Y , Yamashita T , Fujimoto T , Oi S , Moritoh Y , Asakawa T , Kataoka O , Takeuchi K , Suzuki N , Ikedo K , Kosaka T , Tsubotani S , Tani A , Funami M , Amano M , Yamamoto Y , Aertgeerts K , Yano J , Maezaki H
Ref : Bioorganic & Medicinal Chemistry , 19 :172 , 2011
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]ac etyl}-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.
ESTHER : Miyamoto_2011_Bioorg.Med.Chem_19_172
PubMedSearch : Miyamoto_2011_Bioorg.Med.Chem_19_172
PubMedID: 21163664

Title : Discovery of a 3-pyridylacetic acid derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor - Miyamoto_2011_J.Med.Chem_54_831
Author(s) : Miyamoto Y , Banno Y , Yamashita T , Fujimoto T , Oi S , Moritoh Y , Asakawa T , Kataoka O , Yashiro H , Takeuchi K , Suzuki N , Ikedo K , Kosaka T , Tsubotani S , Tani A , Sasaki M , Funami M , Amano M , Yamamoto Y , Aertgeerts K , Yano J , Maezaki H
Ref : Journal of Medicinal Chemistry , 54 :831 , 2011
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]ac etic 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.
ESTHER : Miyamoto_2011_J.Med.Chem_54_831
PubMedSearch : Miyamoto_2011_J.Med.Chem_54_831
PubMedID: 21218817
Gene_locus related to this paper: human-DPP4