Iminopyrimidinones: A novel pharmacophore for the development of orally active renin inhibitors. Issue 7 (1st April 2015)

• Record Type: Journal Article
• Authors: McKittrick, Brian A.; Caldwell, John P.; Bara, Thomas; Boykow, George; Chintala, Madhu; Clader, John; Czarniecki, Michael; Courneya, Brandy; Duffy, Ruth; Fleming, Linda; Giessert, Rachel; Greenlee, William J.; Heap, Charles; Hong, Liwu; Huang, Ying; Iserloh, Ulrich; Josien, Hubert; Khan, Tanweer; Korfmacher, Walter; Liang, Xian; Mazzola, Robert; Mitra, Soumya; Moore, Kristina; Orth, Peter; Rajagopalan, Murali; Roy, Sudipta; Sakwa, Samuel; Strickland, Corey; Vaccaro, Henry; Voigt, Johannes; Wang, Hongwu; Wong, Jesse; Zhang, Rumin; Zych, Andrew;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 7(2015)
• Page Start: 1592
• Page End: 1596
• Publication Date: 2015-04-01
• Subjects: Renin inhibitors -- BACE1 -- Hypertension -- Structure-based drug design -- Enzyme inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.02.003
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this Letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor. Abstract: The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.