Synthesis and structure-activity relationships of human renin inhibitors designed from angiotensinogen transition state
| Autor: | Iwao Shimaoka, Kenji Akahane, Tetsuhiro Kubota, Tetsuhide Kamijo, Toshiaki Yamaguchi, Makoto Murakami, Hideaki Umeyama, Atsushi Tsubaki, Yoshiaki Kiso, Kinji Iizuka, Yasuo Etoh, Akira Iyobe, Hiromu Harada |
|---|---|
| Rok vydání: | 1990 |
| Předmět: |
Stereochemistry
medicine.drug_class Molecular Sequence Data Angiotensinogen Cathepsin D Renin inhibitor Structure-Activity Relationship Valine Drug Discovery Renin–angiotensin system Renin medicine Structure–activity relationship Animals Humans Amino Acid Sequence Binding Sites Sheep biology Chemistry Active site Biological activity General Chemistry General Medicine Biochemistry Enzyme inhibitor biology.protein |
| Zdroj: | Chemicalpharmaceutical bulletin. 38(9) |
| ISSN: | 0009-2363 |
| Popis: | The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P1-P1', P2, and P4-P3. Decrease in the size of side chain alkyl group in norstatine analog at P1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P2, inhibited potently cathepsin D (IC50 = 6.0 x 10(-9) M) and pepsin (IC50 = 3.5 x 10(-7) M) to the same extent as renin (IC50 = 8.5 x 10(-10) M), and thus was not specific for renin. The reduction of the beta-carbonyl group to methylene group in beta-carbonylpropionyl residue at P4-P3 decreased the potency about 2 orders against human renin (5i: IC50 = 1.1 x 10(-7) M vs. 1: IC50 = 2.4 x 10(-9) M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented. |
| Databáze: | OpenAIRE |
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