Asymmetric preference of serine proteases toward phosphonate and phosphinate esters.
We have previously reported the asymmetric synthesis of (alpha-aminoalkyl) diphenylphosphonate and phosphinate derivatives designed as inhibitors of chymotrypsin- and elastase-like proteases. This paper reports the first kinetic evaluation of individual epimers of the (alpha-aminoalkyl) diphenylphosphonates as inactivators of chymotrypsin, cathepsin G and neutrophil elastase (HNE). Results show that the (R)-epimers consistently function as more potent irreversible inactivators of their respective target proteases than the corresponding (S)-epimers. Additionally, phosphinate analogues were found to be consistently superior to their diphenylphosphonate counterparts. For example, Cbz. Phe(P)(OPh)-(CH(2))(2)-CO(2)Et inactivates cathepsin G approximately 45-fold more rapidly (k(i)/K(i) = 1.2 x 10(5) M(-1). min(-1)) than the analogous Cbz.Phe(P)(OPh)(2) (2.6 x 10(3) M(-1). min(-1)). Similarly, Cbz.Val(P)(OPh)-(CH(2))(2)-CO(2)Et was found to inactivate HNE some 3-fold more efficiently than Cbz.Val(P)(OPh)(2) (6.5 x 10(3) and 2.0 x 10(3) M(-1). min(-1), respectively).
Walker
B
B
Division of Biomedicinal Chemistry, School of Pharmacy, Medical Biology Centre, 97 Lisburn Road, Belfast, Northern Ireland, BT9 7BL, United Kingdom.
Wharry
S
S
Hamilton
R J
RJ
Martin
S L
SL
Healy
A
A
Walker
B J
BJ
D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002648:Child; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D003550:Cystic Fibrosis / Q000201:enzymology; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007536:Isomerism; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D063065:Organophosphonates / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010721:Phosphinic Acids / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity
D063065:Organophosphonates; D010721:Phosphinic Acids; D015842:Serine Proteinase Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase