Potential protease inhibitors based on a functionalized cyclic sulfamide scaffold.
Exploratory studies related to the design and synthesis of functionalized cyclic sulfamides (I) as potential inhibitors of proteolytic enzymes were carried out. The structural motif and three diversity sites embodied in the scaffold render it amenable to combinatorial parallel synthesis and the facile generation of lead discovery prospecting libraries. The scaffold was readily assembled starting with (DL) serine methyl ester, and a series of compounds was generated and screened against human leukocyte elastase. Modification of the P(1) recognition element, believed to be accommodated at the primary specificity site (S(1) subsite) of the enzyme, yielded compounds that inhibited the enzyme by an apparent hyperbolic partial mixed-type inhibition.
Zhong
Jiaying
J
Department of Chemistry, Wichita State University, Wichita, Kansas 67260, USA.
Gan
Xiangdong
X
Alliston
Kevin R
KR
Lai
Zhong
Z
Yu
Hongyi
H
Groutas
Christopher S
CS
Wong
Tzutshin
T
Groutas
William C
WC
D000577:Amides / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry*
D000577:Amides; D011480:Protease Inhibitors; D013440:Sulfides; D019272:Leukocyte Elastase