Design and synthesis of potent macrocyclic renin inhibitors |
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Authors: | Sund Christian Belda Oscar Wiktelius Daniel Sahlberg Christer Vrang Lotta Sedig Susanne Hamelink Elizabeth Henderson Ian Agback Tatiana Jansson Katarina Borkakoti Neera Derbyshire Dean Eneroth Anders Samuelsson Bertil |
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Institution: | Medivir AB, PO Box 1086, SE-14122 Huddinge, Sweden |
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Abstract: | 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 Ki and the human plasma renin activity (HPRA)IC50 was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (Ki = 3.3 nM and HPRA IC50 = 7 nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (Ki = 34 nM and HPRA IC50 = 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. |
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Keywords: | Renin Aspartyl protease Macrocycle Antihypertensive Peptidomimetic Cathepsin D BACE-1 |
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