3OWN

Potent macrocyclic renin inhibitors

Summary for 3OWN

• Entry DOI: 10.2210/pdb3own/pdb
• Descriptor: Renin, ACETATE ION, SODIUM ION, ... (6 entities in total)
• Functional Keywords: renin, protease, aspartyl protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76419.15

Authors

Borkakoti, N.,Derbyshire, D. (deposition date: 2010-09-20, release date: 2010-12-15, Last modification date: 2024-11-20)

Primary citation

Sund, C.,Belda, O.,Wiktelius, D.,Sahlberg, C.,Vrang, L.,Sedig, S.,Hamelink, E.,Henderson, I.,Agback, T.,Jansson, K.,Borkakoti, N.,Derbyshire, D.,Eneroth, A.,Samuelsson, B.
Design and synthesis of potent macrocyclic renin inhibitors.
Bioorg.Med.Chem.Lett., 21:358-362, 2011

PubMed 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 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.

PubMed: 21112780
DOI: 10.1016/j.bmcl.2010.10.140

Experimental method

X-RAY DIFFRACTION (2 Å)