Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor

• Published in: Journal of medicinal chemistry Vol. 65; no. 16; pp. 10882 - 10897
• Main Authors: Iijima, Daisuke, Sugama, Hiroshi, Takahashi, Yoichi, Hirai, Miki, Togashi, Yuko, Xie, Jianshu, Shen, Jingkang, Ke, Ying, Akatsuka, Hidenori, Kawaguchi, Takayuki, Takedomi, Kei, Kashima, Akiko, Nishio, Masashi, Inui, Yosuke, Yoneda, Hikaru, Xia, Guangxin, Iijima, Toru
• Format: Journal Article
• Language: English
• Published: American Chemical Society 25-08-2022
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00834

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.