ABSTRACT
Anilinoquinazolines currently of interest as inhibitors of tyrosine kinases have been found to be allosteric inhibitors of the enzyme fructose 1,6-bisphosphatase. These represent a new approach to inhibition of F16BPase and serve as leads for further drug design. Enzyme inhibition is achieved by binding at an unidentified allosteric site.
Subject(s)
Aniline Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Fructose-Bisphosphatase/antagonists & inhibitors , Quinazolines/pharmacology , Allosteric Regulation/drug effects , Allosteric Site , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Animals , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Kidney/enzymology , Liver/enzymology , Models, Molecular , Molecular Structure , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity RelationshipABSTRACT
A series of 5-phenyl-3-ureidobenzazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 4-phenyl-1-tetralone as a key step. Structure-activity relationship studies revealed the importance of the 5-phenyl group for potent and selective CCK-B affinity. Addition of an 8-methyl substituent and resolution provided the potent (CCK-B IC50 = 0.48 nM) CCK-B antagonist 4. The role of the 5-phenyl group as part of a "privileged structure" for high-affinity receptor antagonism is discussed.
