7XGO

Human renin in complex with compound2

Summary for 7XGO

• Entry DOI: 10.2210/pdb7xgo/pdb
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, UNKNOWN LIGAND, ... (4 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, hydrolase
• 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: 2022-08-31, Last modification date: 2024-10-16)

Primary citation

Iijima, D.,Sugama, H.,Awai, N.,Takahashi, Y.,Togashi, Y.,Takebe, T.,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 Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors.
Acs Med.Chem.Lett., 13:1351-1357, 2022

PubMed Abstract: The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound was highly potent despite not occupying S1'-S2' sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.

PubMed: 35978678
DOI: 10.1021/acsmedchemlett.2c00280

Experimental method

X-RAY DIFFRACTION (2.1 Å)