PMID: 11312926Apr 21, 2001Paper

Development of orally active nonpeptidic inhibitors of human neutrophil elastase

Journal of Medicinal Chemistry
K OhmotoM Wieczorek

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.

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Citations

Mar 10, 2004·Bioorganic & Medicinal Chemistry Letters·Robert B PerniYunyi Wei
Jun 4, 2013·European Journal of Medicinal Chemistry·Kikkeri P HarishBasavapatna N Prasanna Kumar
Jul 20, 2002·Bioorganic & Medicinal Chemistry Letters·Christopher A WilloughbyNancy A Thornberry
Jun 26, 2003·Bioorganic & Medicinal Chemistry Letters·Michael S SouthJohn J Parlow
Oct 26, 2006·Journal of the American Chemical Society·F Anthony RomeroDale L Boger
Mar 19, 2011·Journal of Medicinal Chemistry·Nicholas A Meanwell
Aug 21, 2002·American Journal of Respiratory and Critical Care Medicine·Takashige KurakiMinoru Yoshida
Jun 27, 2002·Expert Opinion on Investigational Drugs·Hiroyuki Ohbayashi
Jun 18, 2011·Medicinal Research Reviews·Susana D LucasRui Moreira
Aug 29, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Cledualdo Soares de OliveiraPetrônio Filgueiras de Athayde-Filho
Feb 10, 2021·Journal of Medicinal Chemistry·Ute F RöhrigVincent Zoete
Aug 21, 2010·The Journal of Physical Chemistry. B·Javier G WarrenJuan Torras

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