2666 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 15
Communications to the Editor
D.-L.; Foreman, J . E.; Eveleth, D. D.; Powers, J . C. Novel
Peptidyl R-Keto Amide Inhibitors of Calpains and Other Cys-
teine Proteases. J . Med. Chem. 1996, 39, 4089-4098. (d)
Harbeson, S. L.; Abelleira, S. M.; Akiyama, A.; Barrett, R., III,;
Carroll, R. M.; Straub, J . A.; Tkacz, J . N.; Wu, C.; Musso, G. F.
Stereospecific Synthesis of Peptidyl R-Keto Amides as Inhibitors
of Calpain. J . Med. Chem. 1994, 37, 2918-2929. (e) Li, Z.; Patil,
G. S.; Golubski, Z. E.; Hori, H.; Tehrani, K.; Foreman, J . E.;
Eveleth, D. D.; Bartus, R. T.; Powers, J . C. Peptide R-Keto Ester,
R-Keto Amide, and R-Keto Acid Inhibitors of Calpains and Other
Cysteine Proteases. J . Med. Chem. 1993, 36, 3472-3480.
(5) (a) Chatterjee, S.; Ator, M. A.; Bozyczko-Coyne, D.; J osef, K.;
Wells, G.; Tripathy, R.; Iqbal, M.; Bihovsky, R.; Senadhi, S. E.;
Mallya, S.; O’Kane, T. M.; McKenna, B. A.; Siman, R.; Mallamo,
J . P. Synthesis and Biological Activity of a Series of Potent
Fluoromethyl Ketone Inhibitors of Recombinant Human Calpain
I. J . Med. Chem. 1997, 40, 3820-3828. (b) Angliker, H.; Anagli,
J .; Shaw, E. Inactivation of Calpain by Peptidyl Fluoromethyl
Ketones. J . Med. Chem. 1992, 35, 216-220. (c) Crawford, C.;
Mason, R. W.; Wickstrom, P.; Shaw, E. The Design of Peptidyl-
diazomethane Inhibitors to Distinguish between the Cysteine
Proteinases Calpain II, Cathepsin L, and Cathepsin B. Biochem.
J . 1988, 253, 751-758. (d) McGowan, E. B.; Becker, E.; Detwiler,
T. C. Inhibition of Calpain in Intact Platelets by the Thiol
Protease Inhibitor E-64d. Biochem. Biophys. Res. Commun.
1989, 158, 432-435. (e) Huang, Z.; McGowan, E. B.; Detwiler,
T. C. Ester and Amide Derivatives of E64c as Inhibitors of
Platelet Calpains. J . Med. Chem. 1992, 35, 2048-2054. (f)
Harris, A. L.; Gregory, J . S.; Maycock, A. L.; Graybill, T. L.; Osifo,
I. K.; Schmidt, S. L.; Dolle, R. E. Characterization of a Continu-
ous Fluorogenic Assay for Calpain I. Kinetic Evaluation of
Peptide Aldehydes, Halomethyl Ketones and (Acyloxy)Methyl
Ketones as Inhibitors of the Enzyme. Bioorg. Med. Chem. Lett.
1995, 5, 393-398. (g) For subsite nomenclature for peptide-based
inhibitors, see: Schechter, I.; Berger, A. On the Size of the Active
Site in Protease. 1. Papain. Biochem. Biophys. Res. Commun.
1967, 27, 157-162.
Con clu sion . In this paper, we described a series of
novel and potent calpain inhibitors incorporating N-
alkyl- or -arylsulfonyl-D-amino acids at P2. To our
knowledge, this is unprecedented in the design of
substrate-based potent cysteine protease inhibitor. The
compounds are cell-permeable and inhibit intracellular
calpain I in a human cell line. This study reveals for
the first time that, contrary to literature evidence, the
presence of L-Leu or L-Val residue at P2 is not a
preferred structural requirement for a potent calpain I
inhibitor; an N-alkyl- or -arylsulfonyl-D-amino acid at
P2 can bind with high affinity.
Ack n ow led gm en t. We thank Dr. J effry Vaught for
his support and encouragement and Dr. J ames C. Kauer
for critical review of the manuscript. We are pleased to
acknowledge SmithKline Beecham Pharmaceuticals for
partial support of this research.
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