The Discovery of Piragliatin, a Glucokinase Activator - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 56

Figure 3.6 Single-crystal X-ray structure of 2a.

lacking the urea carbonyl that we surmised may accept a hydrogen bond from
glucokinase, also failed to activate GK. The thiourea analog 7 (SC 1.5 ¼ 3.8 mM)
lost about four-fold in potency relative to the urea 2, possibly as a reflection
of the reduced capacity of the sulfur atom to accept a hydrogen bond. The
C a -methylated analog 8 was also inactive, suggesting a steric effect between
the C a -methyl and the N-acylurea moiety, preventing it from making a pro-
ductive interaction with GK. Collectively, these observations suggested that
the cyclic, intramolecularly hydrogen bonded conformation adopted by the
N-acylureas was necessary to support optimal donor-acceptor hydrogen
bonding with GK.
Later, modeling experiments with the N-acylurea GK activators using the
X-ray co-crystal structures of other GK-GK activator complexes identified
key donor-acceptor H-bond interactions with the backbone NH and carbonyl
of the Arg63 residue in GK, as shown in Figure 3.8. 14 These observations
led to a hypothesis that amides derived from heterocyclic amines of formula I