The Discovery of Piragliatin, a Glucokinase Activator - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 68

clearly indicated the superior potency of 33 over 32, and led to the selection of the
(R,R)- diastereomer 33, piragliatin, 20 as the clinical lead.
3.4 Clinical Proof-of-concept
Piragliatin, in a battery of in vitro and in vivo ecacy tests, PK, and toxicology
profiling in rats and dogs, was superior to the earlier clinical lead 9a, and was
advanced to clinical testing. In a Phase I proof-of-concept study, 21b piragliatin
was evaluated in 15 T2D patients at 25 and 100mg (po, qd) and in a subsequent
multiple ascending dose study at doses ranging from 25mg to 400mg either qd
or bid in T2D patients. 21a In these trials, piragliatin decreased fasting and post-
OGTT glucose levels, 21 improved the insulin secretory profile, increased b-cell
sensitivity to glucose, and decreased hepatic glucose output. Following com-
pletion of Phase II clinical studies, a decision was made not to develop pir-
agliatin further. Based on the experience from piragliatin, Roche is continuing
development of other GK activators.
3.5 Outlook and Conclusion
GK's key role in glucose homeostasis has long been recognized. Developments
over the past decade, including the discovery of MODY-2, PNDM, and PHHI-
related GK mutations, and discovery of novel GK activators and their co-
crystal structures with GK, have significantly enhanced the understanding of
GK structure and function. Nearly 100 patent applications and 10 papers
reporting the characterization of lead molecules have been published to date.
GK activators from several companies, including Merck-Banyu, AstraZeneca,
Lilly, and Array Biopharma, are reported to be in Phase I or II stages of clinical
development. In the next few years, we look forward to understanding the
impact of GK activator therapy on glycemic control and safety in T2D
patients, and specifically their differentiation from the widely prescribed
sulfonylureas.
Acknowledgements
The authors thank Stephen To for editing this article and to Christophe Arbet-
Engels for helpful discussions on the clinical data.
References
1. R. A. DeFronzo, Diabetes, 2009, 58, 773-795.
2. J. Grimsby, F. M. Matschinsky and J. F. Grippo, in Glucokinase and
Glycemic Disease: From Basics to Novel Therapeutics, ed. F. M. Mat-
schinsky and M. A. Magnuson, Karger, Basel, Switzerland, 2004, pp. 360-
378.