7XGP

Human renin in complex with compound3

Summary for 7XGP

• Entry DOI: 10.2210/pdb7xgp/pdb
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, UNKNOWN LIGAND (3 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 74976.43

Authors

Kashima, A. (deposition date: 2022-04-05, release date: 2022-09-07, Last modification date: 2024-10-23)

Primary citation

Iijima, D.,Sugama, H.,Takahashi, Y.,Hirai, M.,Togashi, Y.,Xie, J.,Shen, J.,Ke, Y.,Akatsuka, H.,Kawaguchi, T.,Takedomi, K.,Kashima, A.,Nishio, M.,Inui, Y.,Yoneda, H.,Xia, G.,Iijima, T.
Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor.
J.Med.Chem., 65:10882-10897, 2022

PubMed Abstract: Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative . In our efforts to improve the pharmacokinetic profile of without a significant increase in the MW, we discovered compound (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.

PubMed: 35939295
DOI: 10.1021/acs.jmedchem.2c00834

Experimental method

X-RAY DIFFRACTION (2.65 Å)