1448
P. D. Boatman et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1445–1449
Table 3. Thrombin activity of selected acid and methyl ester analo-
gues
Table 4. Thrombin activity of selected esters and amides
R4X
Thrombin Ki (nM)
Compd
Nu
Thrombin Ki (nM)
R1=A R1=B
Ar
4-Br-Ph
4-Cl-Ph
3,4-di-Cl-Ph
R4
CH3
H
CH3
H
EtO
I-PrO
c-HexO
0.27
0.087
1.5
NA
1.5
0.057
28
53
87
5a,b,c,d
6a,b,cd
7a,b,c,d
8a,b,c,d
10a,b,c,d
13a,b,c,d
4-Br-PhS
4-Cl-PhS
4-CH3O-PhS
3,4-diCl-PhS
PhS
0.023
0.325.7
0.75
0.24
2.9
2.6
83
NA
82 32
4.7
13
36
53
80
78
32
28
29
22
15
11
30
39
24
18
CyclohexylS
91
7.7
NA
and esters then carried out the remainder of the synth-
esis in solution using the acid 23 (Scheme 5). Esters
(ethyl, isopropyl, and cyclohexyl) uniformly underwent
a-addition under mild conditions as described for the
methyl and t-butyl esters. However, treatment of 1 with
propiolate amides (pyrrolidyl, piperidyl and morpholyl)
under the typical reaction conditions did not produce
any of the desired product. Heating the reaction mixture
to 70 ꢀC for several days to effect a-addition to propio-
late amides afforded the product in moderate yields (30–
50% yield).
the Michael addition of thiols and amines has provided
a valuable method for the rapid generation and optimi-
zation of lead compounds. The scope of this reaction
sequence has been investigated and it has been found
that propiolate esters readily undergo a-addition of the
urazole while amides are more resistant to addition but
undergo addition under more vigorous conditions. A
variety of nucleophiles may be added to the resulting
unsaturated esters and amides to produce novel pro-
tease inhibitors in a high-throughput fashion. The ease
of synthesis and general high purity of the products
results in a valuable method for the production of bio-
logically relevant compounds that have potential as
therapeutic agents or leads for the development of such.
We have used information gathered from these studies
to optimize the drug qualities of a series of thrombin
inhibitors. We have also employed this strategy for the
synthesis of inhibitors of a number of proteases. These
will be reported in future publications.
Table 4 summarizes results for determination of throm-
bin inhibition with these analogues. The steric bulk of
the ester has little effect on thrombin inhibition suggest-
ing that the ester group may be oriented toward bulk
solvent. The amide analogues were slightly less active
than the esters. The primary amide analogue of com-
pound 5b was synthesized (R4X=NH2) and the throm-
bin Ki was determined to be 0.19 nM versus 2.6 nM for
5b. The effect of disubstitution on the amide is more
pronounced as can be seen from the data for pyrolidinyl
and morpholinyl amides for which the thrombin inhibi-
tion activity is >100-fold less than the primary amide.
References and Notes
In summary, the a-addition of propiolates to urazoles
for the production of unique b-strand mimetics has been
developed. Utilization of the intermediate acrylates for
1. (a) For reviews on thrombin inhibitors, see: Das, J.; Kim-
ball, S. E. Bioorg. Med. Chem. 1995, 3, 999. (b) Menear, K.
Exp. Opin. Invest. Drugs 1999, 8, 1373. (c) Vacca, J. P. Curr.
Opin. Chem. Biol. 2000, 4, 394.
2. (a) Kim, H.-K.; Kahn, M. Tetrahedron Lett. 1997, 38, 6483.
(b) Boatman, P. D.; Ogbu, C. O.; Eguchi, M.; Kim, H.-O.;
Nakanishi, H.; Cao, B.; Shea, J. P.; Kahn, M. J. Med. Chem.
1999, 42, 1367.
3. Ogbu, C. O.; Qabar, M. N.; Boatman, P. D.; Urban, J.;
Meara, J. P.; Ferguson, M. D.; Tulinsky, J.; Lum, C.; Babu,
S.; Blaskovich, M. A.; Nakanishi, H.; Ruan, F.; Cao, B.;
Minarik, R.; Little, T.; Nelson, S.; Nguyen, M.; Gall, A.;
Kahn, M. Bioorg. Med. Chem. Lett. 1998, 8, 2321.
4. Moriarty, R. M.; Prakash, R. M. I.; Penmasta, R. Synth.
Comm. 1987, 409.
5. Little, T.; Meara, J.; Ruan, F.; Nguyen, M.; Qabar, M.
Synth. Comm. 2002, 32, 1741.
6. Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119,
7595.
7. General procedure: PAL, Wang and Chlorotrityl resins
(Polystyrene, 1% DVB crosslinked core) were used. General
procedure 1: Resin 2suspended in solvent (DCM, CHCl or
3
DCE; the reaction does not work in DMF) at rt was treated
with AcOH (5 equiv), base (3–6 equiv), propiolate ester (5–10
equiv) and TPP (2equiv) and shaken at rt for 10–18 h. Then
the resin was washed with DMF and DCM. The products
Scheme 5. Solution phase synthesis of thrombin inhibitors.