Search

Your search keyword '"TANI, Akiyoshi"' showing total 4 results
Start Over Author "TANI, Akiyoshi" Journal bioorganic medicinal chemistry letters
4 results on '"TANI, Akiyoshi"'

1. Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554.

Author

Maezaki H, Tawada M, Yamashita T, Banno Y, Miyamoto Y, Yamamoto Y, Ikedo K, Kosaka T, Tsubotani S, Tani A, Asakawa T, Suzuki N, and Oi S

Subjects
Animals, Diabetes Mellitus, Type 2 drug therapy, Dipeptidyl Peptidase 4 chemistry, Dipeptidyl Peptidase 4 metabolism, Drug Design, Female, Glucose Tolerance Test, Humans, Molecular Docking Simulation, Rats, Sprague-Dawley, Rats, Wistar, Structure-Activity Relationship, Dipeptidyl-Peptidase IV Inhibitors chemistry, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Pyridines chemistry, Pyridines pharmacology, Quinolines chemistry, Quinolines pharmacology
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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
Full Text
View/download PDF

2. Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors.

Author

Kamata M, Yamashita T, Kina A, Tawada M, Endo S, Mizukami A, Sasaki M, Tani A, Nakano Y, Watanabe Y, Furuyama N, Funami M, Amano N, and Fukatsu K

Subjects
Animals, Enzyme Inhibitors pharmacology, Humans, Microsomes drug effects, Microsomes enzymology, Models, Molecular, Molecular Structure, Pyrazoles pharmacology, Rats, Spiro Compounds pharmacology, Stereoisomerism, Structure-Activity Relationship, Acetyl-CoA Carboxylase antagonists & inhibitors, Enzyme Inhibitors chemistry, Pyrazoles chemistry, Spiro Compounds chemistry
Abstract

Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
Full Text
View/download PDF

3. Design, synthesis, and structure-activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors.

Author

Kamata M, Yamashita T, Kina A, Funata M, Mizukami A, Sasaki M, Tani A, Funami M, Amano N, and Fukatsu K

Subjects
Acetyl-CoA Carboxylase metabolism, Animals, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Humans, Liver metabolism, Piperidines chemical synthesis, Piperidines pharmacokinetics, Rats, Stereoisomerism, Structure-Activity Relationship, Acetyl-CoA Carboxylase antagonists & inhibitors, Drug Design, Enzyme Inhibitors chemical synthesis, Lactones chemistry, Piperidines chemistry, Spiro Compounds chemistry
Abstract

Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3-b]pyridine core exhibited potent ACC inhibitory activity and favorable pharmacokinetic profiles in rats., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
Full Text
View/download PDF

4. Design, synthesis, and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors.

Author

Yamashita T, Kamata M, Endo S, Yamamoto M, Kakegawa K, Watanabe H, Miwa K, Yamano T, Funata M, Sakamoto J, Tani A, Mol CD, Zou H, Dougan DR, Sang B, Snell G, and Fukatsu K

Subjects
Crystallization, Enzyme Inhibitors chemistry, Models, Molecular, Spironolactone chemistry, Structure-Activity Relationship, Acetyl-CoA Carboxylase antagonists & inhibitors, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Spironolactone chemical synthesis, Spironolactone pharmacology
Abstract

The co-crystal structure of the human acetyl-coenzyme A 2 (ACC2) carboxyl transferase domain and the reported compound CP-640186 (1b) suggested that two carbonyl groups are essential for potent ACC2 inhibition. By focusing on enhancing the interactions between the two carbonyl groups and the amino acid residues Gly(2162) and Glu(2230), we used ligand- and structure-based drug design to discover spirolactones bearing a 2-ureidobenzothiophene moiety., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results