2. Academic Validation
  3. Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor

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

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.

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