Utilizing Lexicon’s knockout mice technology, dual inhibition of both sodium-glucose co-transporters 1 and 2 (SGLT1 and SGLT2) was identified as a promising approach to the treatment of metabolic and cardiovascular disease. An extensive Medicinal Chemistry program was initiated which led to the discovery of sotagliflozin, with the optimal profile of SGLT1 and SGLT2 inhibition (SGLT1 IC50 = 36 nM and SGLT2 IC50 = 1.8 nM). Sotagliflozin was well tolerated in Phase 1 and Phase 2 clinical trials. The pivotal SOLOIST-WHF and SCORED Phase 3 studies in more than 10,000 high CV risk patients demonstrated sotagliflozin’s unique profile for the treatment or prevention of heart failure. Recent <i>in vitro</i> studies have further differentiated sotagliflozin’s mechanism of action from selective SGLT2 inhibitors. This presentation will cover the discovery, synthesis, and clinical development of sotagliflozin.  An NDA for sotagliflozin is currently under review at the FDA for the indication of heart failure.

From mouse to man: Discovery and development of sotagliflozin, a dual SGLT1/SGLT2 inhibitor for heart failure

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ACS Spring 2023

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