Communications to the Editor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 3921
lactones 2, 22, and 23 is ascribed in part to their
intrinsic ring strain (see later), the lactams require
additional activation. Thus the sulfonamide analogues
24 and 25 show at least a 1000-fold increase in activity
over the unsubstituted lactam 1. All these compounds
show at least a 10-fold selectivity over other serine
proteases, presumably reflective of the diversity of the
S-1 binding sites in these enzymes.25 However, the
intrinsic activities of these analogues against thrombin,
chymotrypsin and cathepsin G are significant and
enticing. Replacement of the allyl group with substit-
uents derived from the P-1 residues of substrates
normally cleaved by these enzymes may lead to in-
creased potency against those enzymes.
For comparison purposes these compounds were
tested alongside a potent elastase inhibitor from Merck,
L-694,458.26 At the 40-min time point against HNE,
these compounds (except 1) were of similar inhibitory
activity. At the 0-min time point, they are less active
suggestive of slower binding in comparison to
L-694,458. Further kinetics have not been explored as
the IC50 values have only been used for the purpose of
ranking compounds for further biological testing.
stability of the lactams in blood gives confidence that
acceptable concentrations of inhibitor may be possible
after oral administration. We will report further details
of this work shortly.
Ack n ow led gm en t. We would like to thank Laiq
Chaudry for the thrombin assays, Dr. P. Brush for the
chemical stability experiment, Mr. S. Parry and Mr. R.
J . Stubbs for the blood stabilities, Mr. S. J ackson for
the enantiomer separation, and Dr. J . Montana for the
synthesis of 23. We also thank Dr. P. Knox and Dr. E.
McDonald for helpful discussions and support.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and analytical data (20 pages). Ordering information is
given on any current masthead page.
Refer en ces
(1) Sinha, S.; Watorek, W.; Karr, S.; Giles, J .; Bode, W.; Travis, J .
Primary Structure of Human Neutrophil Elastase. Proc. Natl.
Acad. Sci. U.S.A. 1987, 84, 2228-2232.
(2) (a) Merck: Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B.
M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.;
Maycock, A. L.; Osinga, D. G.; Underwood, D. J .; Weston, H.;
Davies, P.; Doherty, J . B. Orally Active â-Lactam Inhibitors of
Human Leukocyte Elastase. 3. Stereospecific Synthesis and
Structure-Activity Relationships for 3,3-Dialkylazetidin-2-ones.
J . Med. Chem. 1995, 38, 2449-2462. (b) Zeneca: Veale, C. A.;
Bernstein, P. R.; Bohnert, C. M.; Brown, F. J .; Bryant, C.;
Damewood, J . R.; Earley, J .; Feeney, S. W.; Edwards, P. D.;
Gomes, B.; Hulsizer, J . M.; Kosmider, B. J .; Krell, R. D.; Moore,
G.; Salcedo, T. W.; Shaw, A.; Silberstein, D. S.; Steelman, G. B.;
Stein, M.; Strimpler, A.; Thomas, R. M.; Vacek, E. P.; Williams,
J . C.; Wolanin, D. J .; Woolson, S. Orally Active Trifluoromethyl
Ketone Inhibitors of Human Leukocyte Elastase. J . Med. Chem.
1997, 40, 3173-3181. (c) Sterling Winthrop: Hlasta, D. J .;
Ackermann, J . H.; Court, J . J .; Farrell, R. P.; J ohnson, J . A.;
Kofron, J . L.; Robinson, D. T.; Talomie, T. G.; Dunlap, R. P.;
Franke, C. A. A Novel Class of Cyclic â-Dicarbonyl Leaving
Groups and Their Use in the Design of Benzisothiazolone
Human Leukocyte Elastase Inhibitors. J . Med. Chem. 1995, 38,
4687-4692. (d) Hoechst: Burkhart, J . P.; Mehdi, S.; Koehl, J .
R.; Angelastro, M. R.; Bey, P.; Peet, N. P. Preparation of R-Keto
Ester Enol Acetates as Potential Prodrugs of Human Neutrophil
Elastase Inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 63-64.
(e) Wichita State University: Kuang, R.; Venkataraman, R.;
Ruan, S.; Groutas, W. C. Use of the 1,2,5-Thiadiazolidin-3-one
1,1 dioxide and Isothiazolidin-3-one 1,1 dioxide Scaffolds in the
Design of Potent Inhibitors of Serine Proteinases. Bioorg. Med.
Chem. Lett. 1998, 8, 539-544.
(3) Vender, R. L. Therapeutic Potential of Neutrophil-Elastase
Inhibition in Pulmonary Disease. J . Invest. Med. 1996, 44, 531-
539.
(4) O′Neill, M. J .; Lewis, J . A.; Noble, H. M.; Holland, S.; Mansat,
C.; Farthing, J . E.; Foster, G.; Noble, D.; Lane, S. J .; Sidebottom,
P. J .; Lynn, S. M.; Hayes, M. V.; Dix, C. J . Isolation of
Translactone-Containing Triterpenes with Thrombin Inhibitory
Activities from the Leaves of Lantana Camara L. (Verbenaceae).
J . Nat. Prod., submitted for publication.
(5) We are unaware of precedent for the systems described. Cyclo-
pentane trans-lactones are known from (a) synthesis: Fuku-
zawa, S.; Lida, M.; Nakanishi, A.; Fujinami, T.; Sakai, S.
Intramolecular Reductive Cyclization of Unsaturated Keto or
Aldo Esters by Samarium(II) Diiodide: A Ready Synthesis of
Bicyclic γ-Lactones. J . Chem. Soc., Chem. Commun. 1987, 920-
921. (b) Natural sources4: Kelecom, A.; Cabral, M. M. O.; Garcia,
E. S. A New Euphane Triterpene from the Brazilian Melia
Azedarach. J . Braz. Chem. Soc. 1996, 7, 39-41.
On the basis of modeling studies of 2 and 25 in the
active site of porcine pancreatic elastase (derived from
known X-ray structures), we propose that the allyl group
docks into the S-1 specificity pocket and the carbonyl
group of the benzyl carbamate hydrogen bonds to the
NH of valine-216 (chymotrypsin numbering).
As already mentioned, a feature of the trans-lactones
and trans-lactams described here is their ring strain.
Thus the infrared lactam and lactone carbonyl stretch-
ing frequencies of 1, 24, 25, 2, and 23 are ν 1713, 1768,
1759, 1791, and 1785 cm-1 respectively, and show a 10-
20-cm-1 shift to higher frequency in comparison to
similar cis-fused systems.17
Empirical observation from aqueous basic and acidic
workups of trans-lactones and trans-lactams suggested
that lactones, in contrast to lactams, were unstable at
basic pH. We therefore examined the stability of the
ethyl carbamate 23 in deuterated water at various pD’s.
Solutions of 23 in 1:1 buffer:acetonitrile at pD 0.8 at 20
or 39 °C showed no decomposition up to 24 h as
monitored by infrared spectroscopy. However at pD 9.3,
23 showed 10% decomposition at 1 h and 60% at 24 h.
By infrared analysis, the decomposition product is the
corresponding hydroxy acid.27
(6) Dowle, M. D.; Finch, H.; Harrison, L. A.; Inglis, G. G. A.;
J ohnson, M. R.; Macdonald, S. J . F.; Shah, P.; Smith, R. A. WO
9736903 A1 971009.
The human plasma and whole blood stabilities of
representative trans-lactones and trans-lactams were
also examined. Thus, the half-lives of 2 and 25 in
human plasma are 6 min and 2 h and in human whole
blood 2 min and 4.5 h, respectively, suggesting that the
lactams are metabolically more robust than the lactones.
In summary, we have described syntheses and activi-
ties of new pharmacophores for HNE inhibition. The
(7) 5 is prepared from propiolic acid by (a) 57% HI, reflux (98%
crude), (b) K2CO3, EtI, DMSO (93% crude). No purification is
necessary; cf. Biougne, J .; Theron, F. â-Haloacrylic Acids.
Reactions with Certain Nucleophiles. C. R. Acad. Sci. Ser. C
1971, 272, 858-861.
(8) Takai, K.; Tagashiri, T.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. Reactions of Alkenylchromium Reagents Prepared
from Alkenyl Trifluoromethanesulfonates (Triflates) with Chro-
mium(II) Chloride under Nickel Catalysis. J . Am. Chem. Soc.
1986, 108, 6048-6050.