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

  • J Med Chem. 2022 Aug 25;65(16):10882-10897. doi: 10.1021/acs.jmedchem.2c00834.
Daisuke Iijima  1 ,  Hiroshi Sugama  1 ,  Yoichi Takahashi  1 ,  Miki Hirai  1 ,  Yuko Togashi  1 ,  Jianshu Xie  2 ,  Jingkang Shen  2 ,  Ying Ke  2 ,  Hidenori Akatsuka  1 ,  Takayuki Kawaguchi  1 ,  Kei Takedomi  1 ,  Akiko Kashima  1 ,  Masashi Nishio  1 ,  Yosuke Inui  1 ,  Hikaru Yoneda  1 ,  Guangxin Xia  2 ,  Toru Iijima  1  3
Affiliations
  • 1. Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
  • 2. Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, PR China.
  • 3. Lead Exploration Unit, Drug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
PMID: 35939295 DOI: 10.1021/acs.jmedchem.2c00834
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.

Products