Phosphonates and phosphinates: novel leaving groups for benzisothiazolone inhibitors of human leukocyte elastase.
A novel class of alkyl and aryl phosphonate and phosphinate acid-based leaving groups has been developed for utilization in the synthesis of benzoisothiazolone (BIT) inhibitors of human leukocyte elastase (HLE). A number of BITs were synthesized with phosphonate and phosphinate acid-based leaving groups and were found to be potent inhibitors of HLE. Compound 3c with a diethyl phosphonate leaving group is the most potent inhibitor synthesized in this series with Ki* = 0.035 nM and ED50 = 2.0 mg/kg.
Desai
R C
RC
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, Pennsylvania 19426, USA.
Court
J C
JC
Ferguson
E
E
Gordon
R J
RJ
Hlasta
D J
DJ
Dunlap
R P
RP
Franke
C A
CA
D006801:Humans; D019272:Leukocyte Elastase; D009943:Organophosphorus Compounds / Q000737:chemistry; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
D009943:Organophosphorus Compounds; D013844:Thiazoles; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; C015699:1,2-benzisothiazoline-3-one