The Discovery of Piragliatin, a Glucokinase Activator - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 51

CHAPTER 3
The Discovery of Piragliatin, a
Glucokinase Activator
RAMAKANTH SARABU, a , * JEFFERSON W. TILLEY a
AND JOSEPH GRIMSBY b
a Departments of Discovery Chemistry, Hoffmann-La Roche, 340 Kingsland
Street, Nutley, NJ 07110, USA; b Metabolic and Vascular Diseases,
Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, USA
3.1 Introduction and Target Background
Type 2 diabetes (T2D) is a metabolic disorder characterized by elevated blood
glucose levels resulting from a combination of pancreatic b-cell dysfunction and
consequent deficiencies in insulin secretion, insulin resistance, and increased
hepatic glucose production. Defects in the ability of the pancreatic b-cell to
secrete insulin in response to a meal and the diminished capacity of the liver and
skeletal muscle to utilize glucose in response to insulin represent core patho-
physiological defects associated with T2D. Other tissues such as adipose, the
gastrointestinal tract, kidney, and brain also contribute to dysglycemia in
patients with T2D. 1 As T2D progresses, patients rely on higher doses of oral
antidiabetic agents, addition of additional drugs to the treatment regimen, and
often require insulin to gain adequate glycemic control. Therefore, more
effective therapeutic agents targeting the multiple pathogenic abnormalities of
T2D along with sustained ecacy represents a major unmet medical need.
Type 2 diabetes has been an area of focus for drug discovery research at
Roche for nearly two decades. As a part of this effort, a Roche research team in
the mid 1990s recognized the important role of glucokinase (GK) in regulating