Download MendeleyDiscovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor.
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.(2022) J Med Chem 65: 10882-10897
- PubMed: 35939295
- DOI: https://doi.org/10.1021/acs.jmedchem.2c00834
- Primary Citation of Related Structures:
7XGP - 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 4 . In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (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.
Organizational Affiliation:
Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
