H. Geneste et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1934–1937
1937
Teschendorf, H. J.; Traut, M.; Unger, L.; Wicke, K. M.;
Weddige, F. K.; Freeman, A. S.; Gross, G. Poster, 32nd
Annual Meeting of the Society for Neuroscience, Orlando,
FL, November 2–7, 2002; Society for Neuroscience:
Washington, DC, 2002; Abs 894.6.;
and selectivity versus D2 was thus maintained at an
insufficient level. Interestingly, when comparing 2 with
22, disubstitution (R2 5 H) induced an increase of
clogP7 (from 4.7 up to 5.1) and in parallel a decrease
2
2
8
˚
˚
of PSA (from 73 A down to 65 A ).
2. Geneste, H.; Backfisch, G.; Braje, W.; Delzer, J.; Haupt,
A.; Hutchins, C. W.; King, L. L.; Kling, A.; Teschendorf,
H.-J.; Unger, L.; Wernet, W. Bioorg. Med. Chem. Lett.
2006, 16, 490.
3. Geneste, H.; Backfisch, G.; Braje, W.; Delzer, J.; Haupt,
A.; Hutchins, C. W.; King, L. L.; Lubisch, W.; Steiner, G.;
Teschendorf, H.-J.; Unger, L.; Wernet, W. Bioorg. Med.
Chem. Lett. 2006, 16, 658.
Unexpectedly, removal of one NH group (compound 6,
X = CH2, Table 4) facilitated high discrimination of the
two receptors (>100-fold).13 Such high selectivities ver-
sus D2 were rarely observed within the parent 1H-pyri-
din-2-one series (X = CH, Tables
1 and 2). As
exemplified by 5, the other NH group seemed to be re-
quired for high selectivity versus D2. Finally, given the
suboptimal PK of 6 (F < 10%),14 activities on that series
were terminated.
4. Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53,
14437.
5. For these examples, amine 1 (1.0 equiv) was treated with
p-nitrophenylchloroformate (1.1 equiv) and DIEA
(1.1 equiv) in a 1:1 mixture of DMA:DCM. The reaction
mixture was stirred at ambient temperature for 1 h. To the
resulting p-nitrophenyl carbamate solution were added the
desired amine (1.25 equiv) and DIEA (2.2 equiv), followed
by heating at 55 ꢁC overnight. The desired urea was
isolated by scavenging the undesired p-nitrophenol by-
product with MP-carbonate resin, filtration, concentra-
tion, and purification by reverse-phase HPLC.
In summary, two novel series of potent and selective
dopamine D3 antagonists have been reported. Within
the 1H-pyridin-2-one series, substitution in position 3
led to compounds (11–13) with low nM D3 affinity
and high selectivity versus D2. Moreover, 7b displayed
oral bioavailability as well as brain penetration in rat.
Within the urea series, removal of one NH group (com-
pound 6) facilitated high discrimination of the D3 and
D2 receptors, although bioavailability (rat) was subopti-
mal. These data significantly enhance our understanding
of the D3 pharmacophore and are expected to lead to
novel approaches for the treatment of schizophrenia.
Further optimization of these two series (1H-pyridin-2-
ones and ureas) will be reported in due course.
6. Wicke, K.; Garcia-Ladona, J. Eur. J. Pharmacol. 2001,
424, 85.
7. Leo, A. J.; Hoekman, D. Perspect. Drug Discovery Des.
2000, 18, 19.
8. The calculation of polar surface area is based on fragment
contributions: Ertl, P.; Rohde, B.; Selzer, P. J. Med.
Chem. 2000, 43, 3714, and references cited therein.
9. Measured in % recovery of parent after 1 h incubation at
37 ꢁC with liver microsomes (0.5 mg/mL microsomal
protein; rat, dog, and human) in the presence of NADPH.
10. Artursson, P. Crit. Rev. Ther. Drug Carrier Syst. 1991, 8,
105; Hilgers, A. R.; Conradi, R. A.; Burton, P. S. Pharm.
Res. 1990, 7, 902.
11. After iv- and po-dosing (2 and 10 mg/kg, respectively).
12. The interactions with the other parts of the molecule are
not shown and not discussed in detail, as they have already
been published for other D3 ligands.2
13. Numerous amides, mostly (hetero)arylamides, are
known in the literature as dopamine D3-receptor antag-
onists: see, for example: Hackling, A.; Ghosh, R.;
Perachon, S.; Mann, A.; Ho¨ltje, H.-D.; Wermuth, C.
G.; Schwartz, J.-C.; Sippl, W.; Sokoloff, P.; Stark, H.
J. Med. Chem. 2003, 46, 3883, and references cited
therein. The closest analog to 6, a 3-phenyl-propiona-
mide described by Hackling et al displayed a low
selectivity versus D2 (ratio Ki (D2)/Ki (D3) of 10).
14. Despite in vitro microsomal stability (rat-human
94–96%).9
Acknowledgments
We thank Stefan Maurus, Karlpeter Orth, Katerina Sar-
ris, and Sonja Triebel for supporting chemical synthesis,
our analytical department, Manfred Nebel, Heidrun
Ga¨rtner, and Beate Rauprich for assay development
and screening, Sylvia Hellwig for the permeability mea-
surements (Caco-2).
References and notes
1. Unger, L.; Ladona, F. J. G.; Wernet, W.; Sokoloff, P.;
Wicke, K. M.; Gross, G. Poster, 32nd Annual Meeting of
the Society for Neuroscience, Orlando, FL, November
2–7, 2002; Society for Neuroscience: Washington, DC,
2002; Abs 894.5. Drescher, K. U.; Ladona, F. J. G.,