Sunday, November 22, 2015

Drugs in Clinical Pipeline: SHR3824

SHR3824 [(1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1] octane-2,3,4-triol] is a novel, oral and selective SGLT2 inhibitor, which is structurally different from other SGLT2 inhibitors (flozins) that are currently available or in the late stages of clinical development.

In vitro, SHR3824 potently inhibits human SGLT2, but exerts much weak inhibition on human SGLT1 (IC50 hSGLT2, hSGLT1 = 2.38 and 4324 nM, respectively) showing a selectivity of 1817 for SGLT2. Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg.d) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice [1].

SHR3824 is discovered by Shanghai Hengrui Pharmaceuticals Co, Ltd, (Shanghai) and is currently in Phase I clinical studies in China  for treatment of type 2 diabetes (T2DM).

1. Yan, P. K.; et. al. SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models. Acta Pharmacol Sin 2014, 35(5), 613-624.