J. R. Young et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1723±1727
1727
Table 3.
substituent was hydrophobic in nature and this ulti-
mately led to the identi®cation of the 3,4,5-trimethyl-
phenyl analogue (23h), a potent GnRH antagonist with
subnanomolar binding anity and excellent functional
antagonism.
23
Aryl
hGnRH hPI 23
IC50
(nM)
Aryl
hGnRH hPI
IC50
(nM)
IC50
(nM)
IC50
(nM)
a
b
c
0.9
1.1
1.0
3.9
5.0
8.5
7.7
53
e
f
0.7
0.5
0.7
0.3
6.5
7.1
Acknowledgements
We would like to thank J. Leone, J. Pisano, S. Fabian,
and G. Reynolds for the preparation of several inter-
mediates. We would also like to thank A. Bernick for
mass spectrometry services.
g
h
16.0
2.2
References and Notes
d
1. (a) DeVita, R. J.; Hollings, D. D.; Goulet, M. T.; Wyvratt,
M. J., Jr.; Fisher, M. H.; Lo, J.; Yang, Y. T.; Cheng, K.;
Smith, R. G. Bioorg. Med. Chem. Lett. 1999, 9, 2615. (b)
DeVita, R. J.; Goulet, M. T.; Wyvratt, M. J., Jr.; Fisher, M.
H.; Lo, J.; Yang, Y. T.; Cheng, K.; Smith, R. G. Bioorg. Med.
Chem. Lett. 1999, 9, 2621. (c) Walsh, T. F.; Toupence, R. B.;
Young, J. R.; Huang, S. X.; DeVita, R. J.; Goulet, M. T.;
Wyvratt, Jr., M. J.; Fisher, M. H.; Lo, J.-L.; Cui, J.; Ren, N.;
Yudkovitz, J. B.; Yang, Y. T.; Cheng, K.; Smith, R. G.
Bioorg. Med. Chem. Lett. 2000, 10, 443.
12hh had binding anities <1 nM in the rat and both
analogues were 7 times more potent than 12a in the rLH
assay. Other pyrimidine isomers, such as 12 and 12ii,
which have no net dipole, were not active in the rLH
assay (at concentrations of 1 mM). Replacement of the
urea nitrogen directly attached to the quinolone core
with a methylene (26) was not potency enhancing,
although removal of the urea nitrogen attached to the
heterocycle led to amides 14a±c, which were equipotent to
or better than their corresponding urea counterparts.
Finally, reversing the amide connectivity of 14c furnished
23a, which was 2 times more potent in the binding assay
(hGnRH) and 4 times more potent in the PI assay than
14c. This pyrimidine-carboxamide was found to be the
superior C(6)-substituent.
2. For the preparation of the indanephenylacetic acid and the
3,4,5-trimethylphenylacetic acid, the syntheses began with the
phenols which were processed according to the following 4-
step sequence.
3. Nodi, E. A.; Tanabe, K.; Seyfried, C.; Matsura, S.; Kondo,
Y.; Chen, E. H.; Tyagi, M. P. J. Med. Chem. 1971, 14, 921.
4. Racemic N-BOC-2(20-hydroxyethyl)-piperidine 8 was pre-
pared by protection of the free-amine using standard condi-
tions (BOC2O, NEt3, CH2Cl2). The S-enantiomer of 8 was
prepared by Arndt±Eistert homologation of N-BOC (S)-pipe-
colic acid.
5. Kalir, A.; Mualem, R. Synthesis 1987, 514.
6. Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989,
949.
7. Wilcox, C. F. Jr.; Weber, K. A. J. Org. Chem. 1986, 51,
1088.
8. Due to diculties encountered in puri®cation of the initial
aldehyde product, the crude aldehyde was reduced to the
alcohol which was isolated cleanly.
9. Reetz, M. T.; Kyung, S. H.; Hullman, M. Tetrahedron
1986, 42, 2931.
10. Cacchi, S.; Lupi, A. Tetrahedron Lett. 1992, 33, 3939.
11. For detailed information on rat and human based assays
for receptor binding and function, see ref 1c.
12. Prepared by carbomethoxylation of 5-bromopyrimidine
((Ph3P)2PdCl2, NEt3, DMF-MeOH, CO (1 ATM), 90 ꢀC
(44%)) followed by saponi®cation of the ester (NaOH; HCl
(85%)): Godefroi, E. F. J. Org. Chem. 1962, 27, 2264.
13. 4-Carboxypyrimidine was prepared by reaction of 4-methyl-
pyrimidine with SeO2/pyridine (39%): Archer, G. A.; Kalish, R.
I.; Ning, R. Y.; Sluboski, B. C. J. Med. Chem. 1977, 20, 1312.
With the C(6) position optimized, we returned to the
C(3)-aryl position for further re®nement. Compounds
23b±e are hybrids of the best aryl substitution patterns
found in Table 1 with the preferred C(6)-substituent
from Table 2. The SAR in this series correlated with pre-
vious observations, in which the 3,5- and 3,4-dimethyl
(23a and 23e) and dichloro (23b±c) designs were the most
potent and indeed, nearly equivalent to one another
(Table 3). The activities of iodo-methyl analogue 23f were
indistinguishable from 23a. Attempts to improve the
potency of 23e by incorporating the methyl groups in an
indane framework (23g) resulted in a slight loss of func-
tional antagonism. The similar in vitro pro®les of the 23a
and 23e suggested the preparation of the 3,4,5-trimethyl-
phenyl hybrid (23h).3 Gratifyingly, 23h gave improved
binding and functional antagonist activity compared to
the disubstituted analogues.
In conclusion, a thorough study of the SAR at the C(3)-
aryl position indicated the distinct preference for 3,4- or
3,5-dialkyl or di-halo substituted aromatics. Based upon
the initial SAR, we discovered that the optimal aryl