Development of Orally Active Nonpeptidic Inhibitors of Human Neutrophil Elastase

Abstract

5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha-keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-l(F), 11d,e,k(H), 21d,e,k(F), and 21d,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure-activity relationships (SARs) are discussed.

Oxadiazoles

“…Monosubstituted oxadiazoles are deprotonated at the ring carbon atom to give the corresponding anion, which has been subsequently alkylated with various alkylating agents. Thus, for example, 2-substituted-1,3,4-oxadiazoles 959 after treatment with butyllithium in the presence of MgBr 2 diethyl etherate in THF, [613,614].…”

Unexpected Active-Site Flexibility in the Structure of Human Neutrophil Elastase in Complex with a New Dihydropyrimidone Inhibitor

“…A potent, selective, and orally active inhibitor of neutrophil elastase is believed to inhibit the progression of the long-term lung function decline in COPD patients by inhibition of neutrophilinduced upregulation of pro-inflammatory chemokines, such as interleukin-8, and by inhibition of elastase-mediated lung tissue destruction. 2,6,[10][11][12][13][14] In addition to COPD, HNE is associated with several severe medical conditions, for example, cystic fibrosis, 15,16 ischemia reperfusion injury, 17 and acute respiratory distress syntrome, 18,19 and has been found to promote tumor development and metastasis. 20,21 Despite of its high medicinal relevance and many biochemically characterized inhibitors, 13,22,23 only a limited number of crystal structures of HNE have been published.…”

Current methods for the synthesis of 2-substituted azoles

“…206 Methods to circumvent this ambident nucleophilicity include transmetallation with zinc and inclusion of copper(I) iodide (Scheme 110), 207 Oxadiazoles 250 have been prepared in two steps from simple esters, metallated (Scheme 114) and trapped with Boc-L-valinal in a preparation of human neutrophil elastase inhibitors. 235 A hypervalent coupling reaction 236 is known to occur between lithiated thiazole and thionyl chloride, to provide a mixture of the desired coupling product 253 along with two side products (Scheme 115).…”