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Publication Abstract from PubMed

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)=3.3nM and HPRA IC(50)=7nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (K(i)=34nM and HPRA IC(50)=56nM). 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.

Design and synthesis of potent macrocyclic renin inhibitors.,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 Bioorg Med Chem Lett. 2010 Nov 5. PMID:21112780^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.