Korean J Physiol Pharmacol.  2019 Jan;23(1):55-62. 10.4196/kjpp.2019.23.1.55.

Pharmacological evaluation of HM41322, a novel SGLT1/2 dual inhibitor, in vitro and in vivo

• Lee KH
• Lee SD
• Kim N
• Suh KH
• Kim YH
• Sim SS

• KMID: 2443616
• DOI: http://doi.org/10.4196/kjpp.2019.23.1.55

Abstract

HM41322 is a novel oral sodium-glucose cotransporter (SGLT) 1/2 dual inhibitor. In this study, the in vitro and in vivo pharmacokinetic and pharmacologic profiles of HM41322 were compared to those of dapagliflozin. HM41322 showed a 10-fold selectivity for SGLT2 over SGLT1. HM41322 showed an inhibitory effect on SGLT2 similar to dapagliflozin, but showed a more potent inhibitory effect on SGLT1 than dapagliflozin. The maximum plasma HM41322 level after single oral doses at 0.1, 1, and 3 mg/kg were 142, 439, and 1830 ng/ml, respectively, and the T(1/2) was 3.1 h. HM41322 was rapidly absorbed and reached the circulation within 15 min. HM41322 maximized urinary glucose excretion by inhibiting both SGLT1 and SGLT2 in the kidney. HM41322 3 mg/kg caused the maximum urinary glucose excretion in normoglycemic mice (19.32±1.16 mg/g) at 24 h. In normal and diabetic mice, HM41322 significantly reduced glucose excursion. Four-week administration of HM41322 in db/db mice reduced HbA1c in a dose dependent manner. Taken together, HM41322 showed a favorable preclinical profile of postprandial glucose control through dual inhibitory activities against SGLT1 and SGLT2.

Keyword

Dapagliflozin; Diabetes mellitus; HM41322; SGLT1/2 dual inhibitor

MeSH Terms

Animals
Diabetes Mellitus
Glucose
In Vitro Techniques*
Kidney
Mice
Plasma
Glucose

Figure

• 

  Fig. 1 Chemical structure of HM41322.

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  Fig. 2 Effects of HM41322 on glucose transport mediated by SGLT1 or SGLT2 in vitro. [14C]-AMG uptake by HEK293 cells overexpressing human SGLT1 (A) and SGLT2 (B). Data are expressed as the mean±S.E.M. of four independent experiments.

• 

  Fig. 3 Pharmacokinetic characteristics of HM41322 and dapagliflozin. Plasma concentrations of HM41322 and dapagliflozin were measured at various time points following single oral administrations to mice. Data are presented as the mean±S.E.M. (n=3).

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  Fig. 4 Effects of a single administration of HM41322 on glucose tolerance in normoglycemic mice. (A) Time-course changes in blood glucose during an OGTT. HM41322 (0.1, 1, and 3 mg/kg) and dapagliflozin (1 mg/kg) were orally administered to the mice at 30 min before glucose loading (2 g/kg). (B) The area under the blood glucose concentration-time curve (AUC) for 120 min during an OGTT. Data are expressed as mean±S.E.M., n=6, *p<0.01 vs. vehicle control group, #p<0.01 vs. dapagliflozin-treated group.

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  Fig. 5 Effects of a 4-week repeated administration of HM41322 on body weight, blood glucose level, and glucose tolerance in db/db mice. HM41322 (0.1, 1, and 3 mg/kg) and dapagliflozin (1 mg/kg) were orally administered for 4 weeks. (A) Body weight and (B) blood glucose levels during the 4-week study. (C) Time-course changes in blood glucose during an OGTT at 24 h after the last administration. Data are expressed as mean±S.E.M., n =7.

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