Nonpeptidic inhibitors of human neutrophil elastase. 7. Design, synthesis, and in vitro activity of a series of pyridopyrimidine trifluoromethyl ketones.
Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S5-S4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of > 0.1 mg/mL and Ki values of < or = 10 nM.
Edwards
P D
PD
Department of Medicinal Chemistry, ZENECA Pharmaceuticals, Wilmington, Delaware 19850-5437, USA.
Andisik
D W
DW
Strimpler
A M
AM
Gomes
B
B
Tuthill
P A
PA
D000595:Amino Acid Sequence; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D019272:Leukocyte Elastase; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007659:Ketones; D011725:Pyridines; D011743:Pyrimidines; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase