Drugs in Clinical Pipeline: GSK-1614235

GSK-1614235 [3-{[3-(4-{[3-(ß-D-Glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-yl]methyl}-3-methylphenoxy)propyl]amino}-2,2-dimethylpropanamide] is a potent and selective inhibitor of SGLT1. It has inhibition constant (K_i) values of 27 and 8170 nM for human (h) SGLT1 and hSGLT2, respectively. GSK-1614235 is an analog of KGA-2727 and has nearly 2 fold more specificity for SGLT1 than KGA-2727. Also, this specific behaviour towards SGLT1 makes GSK-1614235 an unique inhibitor compared with other molecules that primarily inhibit renal glucose reabsorption via SGLT2 or have dual effects on SGLT1 and SGLT2 [1].

References:
1. Dobbins, R. L.; et. al. Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Am J Physiol Gastrointest Liver Physiol 2015, 308(11), G946-G954.
2. Fushimi, N.; et. al. Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof. US20090203633A1 (synthesis and activity)

Drugs in Clinical Pipeline: KGA-2727

KGA-2727 [3-(3-{4-[3-(beta-D-glucopyranosyloxy)-5-isopropyl-1Hpyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide], is the first reported selective SGLT1 inhibitor which has a pyrazole-O-glucoside structure. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. It has inhibition constant (K_i) values of 97 and 13,600 nM for human (h) SGLT1 and hSGLT2, respectively.

In March 2005, Kissei Pharmaceutical Co., Ltd. and Dainippon Pharmaceutical Co., Ltd. announced that they have entered into a license agreement on "KGA-2727", a novel agent for the treatment of diabetes, which was discovered by Kissei. It was reported than in future, Kissei will continue to conduct non-clinical studies while Dainippon will conduct clinical development and marketing in Japan. Kissei reserves the right to participate in the clinical development to be conducted by Dainippon as well as the right to co-market the agent. Kissei continues to own the right for this agent outside Japan, including the right for development, manufacturing and marketing.

Drugs in Clinical Pipeline: Sotagliflozin

Sotagliflozin [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol] is an orally available, potent dual inhibitor of sodium-glucose transporter-1 (SGLT1) and sodium-glucose transporter-2 (SGLT2), with an in vivo inhibitory concentration (IC₅₀) of 36 nM against human SGLT1 and 1.8 nM against human SGLT2.