The Discovery of Piragliatin, a Glucokinase Activator - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 53

Figure 3.2 Role of glucokinase in the pancreatic b-cell. Reproduced with permission
from Nature, 2001, 414, 788.
In 1989 a Belgian research group discovered a protein in the liver called the
glucokinase regulatory protein (GKRP) that functions as a competitive GK
inhibitor. 4 When bound to GKRP/fructose-6-phosphate, hepatic GK is
sequestered into the nucleus in an inactive state. Under hyperglycemic condi-
tions or when fructose-6-phosphate (F-6-P) is displaced by fructose-1-phos-
phate (F-1-P), a conformational change in GKRP takes place which dissociates
the GK/GKRP complex, releasing GK in its active form (Figure 3.3). 4 This
observation provided a rational basis to seek low molecular weight compounds
which might modulate the GK/GKRP association, via either by design of F-1-P
mimetics or discovery of other small molecules through a high-throughput
screen (HTS).
The biological rationale for this approach was derived from mice with a
genetic disruption of the GK gene 5 and data from humans 6 with loss and gain
of function GK mutations. 7 Loss of function GK mutations causes a type of
diabetes known as maturity onset of diabetes of the young type 2 (MODY-2) 8
or a more severe phenotype presenting at birth referred to as permanent neo-
natal diabetes mellitus (PNDM), 9 while rare activating or gain of function GK
mutations cause persistent hyperinsulinemic hypoglycemia of infancy (PHHI-
GK). 7 At the time this research was initiated, in the mid-1990s, there were no
reports of small-molecule or protein GK activators.