4XX4

Renin in complex with (4S)-4-isopropyl-4-methyl-6-oxo-1-(3-(2-oxo-4-phenylpyrrolidin-1-yl)benzyl)tetrahydropyrimidin-2(1H)-iminium

Summary for 4XX4

• Entry DOI: 10.2210/pdb4xx4/pdb
• Related: 4XX3
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, (2Z,6S)-2-imino-6-methyl-3-{3-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]benzyl}-6-(propan-2-yl)tetrahydropyrimidin-4(1H)-one, ... (4 entities in total)
• Functional Keywords: animals, antihypertensive agents, blood pressure, drug design, enzyme inhibitors, models, molecular, protein conformation, renin, structure-activity relationship, 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: 75592.29

Authors

Orth, P. (deposition date: 2015-01-29, release date: 2015-02-18, Last modification date: 2024-10-09)

Primary citation

McKittrick, B.A.,Caldwell, J.P.,Bara, T.,Boykow, G.,Chintala, M.,Clader, J.,Czarniecki, M.,Courneya, B.,Duffy, R.,Fleming, L.,Giessert, R.,Greenlee, W.J.,Heap, C.,Hong, L.,Huang, Y.,Iserloh, U.,Josien, H.,Khan, T.,Korfmacher, W.,Liang, X.,Mazzola, R.,Mitra, S.,Moore, K.,Orth, P.,Rajagopalan, M.,Roy, S.,Sakwa, S.,Strickland, C.,Vaccaro, H.,Voigt, J.,Wang, H.,Wong, J.,Zhang, R.,Zych, A.
Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors.
Bioorg. Med. Chem. Lett., 25:1592-1596, 2015

PubMed 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.

PubMed: 25728416
DOI: 10.1016/j.bmcl.2015.02.003

Experimental method

X-RAY DIFFRACTION (2.4 Å)