Design and synthesis of potent macrocyclic renin inhibitors
| Autor: | Daniel Wiktelius, Oscar Belda, Susanne Sedig, Katarina Jansson, Bertil Samuelsson, Tatiana Agback, Neera Borkakoti, Elizabeth Hamelink, Anders Eneroth, Dean Derbyshire, Ian R. Henderson, Christian Sund, Christer Sahlberg, Lotta Vrang |
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| Rok vydání: | 2011 |
| Předmět: |
Macrocyclic Compounds
Peptidomimetic Stereochemistry Isostere Clinical Biochemistry Substituent Pharmaceutical Science Crystallography X-Ray Ring (chemistry) Cathepsin D Biochemistry Plasma renin activity Chemical synthesis chemistry.chemical_compound Renin Drug Discovery Aspartic Acid Endopeptidases Humans Protease Inhibitors Molecular Biology Binding Sites Organic Chemistry chemistry Drug Design Lactam Molecular Medicine Selectivity |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 21:358-362 |
| ISSN: | 0960-894X |
| Popis: | Two types of P1-P3-linked macrocyclic renin inhibitors containing the hydroxyethylene isostere (HE) scaffold just outside the macrocyclic ring have been synthesized. An aromatic or aliphatic substituent (P3sp) was introduced in the macrocyclic ring aiming at the S3 subpocket (S3sp) in order to optimize the potency. A 5-6-fold improvement in both the K(i) and the human plasma renin activity (HPRA)IC(50) was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (K(i) = 3.3 nM and HPRA IC(50) = 7 nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (K(i) = 34 nM and HPRA IC(50) = 56 nM). All macrocycles were epimeric mixtures in regard to the P3sp substituent and X-ray crystallographic data of the representative renin macrocycle 43 complex showed that only the S-isomer buried the substituent into the S3sp. Inhibitory selectivity over cathepsin D (Cat-D) and BACE-1 was also investigated for all the macrocycles and showed that truncation of the prime side increased selectivity of inhibition in favor of renin. |
| Databáze: | OpenAIRE |
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