Design and synthesis of potent macrocyclic renin inhibitors Christian Sund ⇑ , Oscar Belda, Daniel Wiktelius, Christer Sahlberg, Lotta Vrang, Susanne Sedig, Elizabeth Hamelink, Ian Henderson, Tatiana Agback, Katarina Jansson, Neera Borkakoti, Dean Derbyshire, Anders Eneroth, Bertil Samuelsson Medivir AB, PO Box 1086, SE-14122 Huddinge, Sweden article info Article history: Received 22 September 2010 Revised 29 October 2010 Accepted 31 October 2010 Available online 5 November 2010 Keywords: Renin Aspartyl protease Macrocycle Antihypertensive Peptidomimetic Cathepsin D BACE-1 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 epi- meric 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. Inhib- itory 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. Ó 2010 Elsevier Ltd. All rights reserved. The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure and in the maintenance of sodium and volume homeostasis. 1 Inappropriate activation of the RAAS, as seen in disease states such as diabetes, is important in hypertension-induced cardiovascular disease and chronic kid- ney disease. 2,3 The aspartyl protease renin catalyzes the first and also rate-limiting cleavage of angiotensinogen in the RAAS and has long been recognized as a prominent target for antihyperten- sive therapy. 4 Since the 1980s a number of generations of linear peptidomimetic renin inhibitors have been developed by pharma- ceutical companies, 5–7 but these compounds were hampered by high molecular weight and poor oral bioavailability. However, this development finally resulted in the linear nonpeptidomimetic ali- skiren as an acceptable compromise between potency and drug- metabolism-pharmacokinetic (DMPK) properties. 8 The linear peptidomimetic compound 1 (Fig. 1), which had ear- lier been synthesized and tested in our laboratory, showed potent renin inhibitory activity (K i = 21 nM and HPRA IC 50 = 38 nM), but characteristically suffered from high MW, low stability in human liver microsomes (HLM) (Clint 260 lL/min/mg) and low perme- ability (Caco-2, p app <0.4  10 6 cm/s). Furthermore, compound 1 had poor selectivity over Cat-D (K i = 3.3 nM) and BACE-1 (IC 50 = 30 nM). One possible way to favorably alter the DMPK prop- erties of a flexible linear compound is to limit the number of 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.10.140 ⇑ Corresponding author. Tel.: +46 8 54683142; fax: +46 8 54683199. E-mail address: christian.sund@medivir.se (C. Sund). S2 S1' S3 H N H N O OH O N S O O O N H O H N O S3' S3sp S2' S1 H N H N R 2 O OH O N S O O X O Y R 1 1 K i = 21 nM; HPRA IC 50 = 38 nM Cat-D K i = 3.3 nM; BACE-1 K i = 30 nM R 2 = Val benzylamide, methyl, isobutyl R 1 = Me, Ph, 4-MeOPh, MeOCH 2 CH 2 CH 2 , MeOCH 2 CH 2 O X = CO, CH 2 CH 2 Y = NH, CH 2 Figure 1. Development of lead compound 1 to the target macrocycles. Bioorganic & Medicinal Chemistry Letters 21 (2011) 358–362 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl