Design, synthesis, and in vitro evaluation of inhibitors of human leukocyte elastase based on a functionalized cyclic sulfamide scaffold.
The design of novel functionalized templates capable of binding to the active site of serine proteases could potentially lead to the development of potent and highly selective non-covalent inhibitors of these enzymes. Using the elastase-turkey ovomucoid inhibitor complex and insights gained from earlier work based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I), a surrogate cyclosulfamide scaffold (II) was used for the first time in the design of reversible inhibitors of human leukocyte elastase. Compounds 7 and 8 were found to be micromolar reversible inhibitors of the enzyme.
Zhong
Jiaying
J
Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
Gan
Xiangdong
X
Alliston
Kevin R
KR
Groutas
William C
WC
D003500:Cyclization; D015195:Drug Design; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D019272:Leukocyte Elastase