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 crysta l 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 trifluo romethyl ketones (TFMKs). These bicyclic inhibitors were designed to e xtend the concept of the related pyridone trifluoromethyl ketones by i ncorporating a rigidly positioned carbonyl group to participate in a h ydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a s caffold to vector substituents toward the S-5-S-4 subsites of the enzy me's extended binding pocket. Furthermore, the heteroatoms of the pyri midine ring generally increase the aqueous solubility of the pyridopyr imidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and se veral inhibitors from this class of compounds possessed aqueous solubi lities of > 0.1 mg/mL and K-i values of less than or equal to 10 nM.