J. L. Gage et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4155–4159
4159
9. Pandit, J. US 2005/0202550 A1.
Acknowledgements
10. (a) Carvalho, S. A.; da Silva, E. F.; de Souza, M. V. N.; Lourenco, M. C. S.; Vicente,
F. R. Bioorg. Med. Chem. Lett. 2008, 18, 538; (b) Mamolo, M. G.; Falagiani, V.;
Zampieri, D.; Vio, L.; Banfi, E. IL Farmaco 2001, 56, 587; (c) Madsen, P.; Ling, A.;
Plew, M.; Sams, C. K.; Knudsen, L. B.; Sidelmann, U. G.; Ynddal, L.; Brand, C. L.;
Andersen, B.; Murphy, D.; Teng, M.; Truesdale, L.; Kiel, D.; May, J.; Kuki, A.; Shi,
S.; Johnson, M. D.; Teston, K. A.; Feng, J.; Lakis, J.; Anderes, K.; Gregor, V.; Lau, J.
J. Med. Chem. 2002, 45, 5755; (d) Beebe, X.; Darczak, D.; Davis-Taber, R. A.;
Uchic, M. E.; Scott, V. E.; Jarvis, M. F.; Stewart, A. O. Bioorg. Med. Chem. Lett.
2008, 18, 2162.
11. PDE10 Assay. Compounds were tested for PDE10 potency by measuring the
inhibition of PDE10 hydrolysis of [3H]cGMP to [3H]GMP. Generally, eight
dilutions of compound were assayed in 50 mM Tris–HCl pH 7.5, 8.3 mM MgCl2,
0.5 mg/mL BSA, 1.7 mM EGTA, 16 nM [3H]cGMP and 1% DMSO. To start the
The authors would like to thank the Stanley Medical Research
Institute for funding.
References and notes
1. Manallack, D. T.; Hughes, R. A.; Thompson, P. E. J. Med. Chem. 2005, 48, 3449.
2. (a) Grootendorst, D. C.; Klaus, R. F. Curr. Opin. Allergy Clin. Immunol. 2002, 2, 61;
(b) Barnes, P. J. Nat. Rev. Drug Disc. 2002, 1, 437; (c) Travadi, J. N.; Patole, S. K.
Pediatr. Pulmonol. 2003, 36, 457; (d) Marko, D.; Pahlke, G.; Merz, K.-H.;
Eisenbrand, G. Chem. Res. Toxicol. 2000, 13, 944; (e) Ghofrani, H. A.; Osterloh, I.
H.; Grimminger, F. Nat. Rev. Drug Disc. 2006, 5, 689; (f) Kass, D. A.; Beavo, J. A.
Circ. Res. 2007, 101, 1084; (g) Menniti, F. S.; Faraci, W. S.; Schmidt, C. J. Nat. Rev.
Drug Disc. 2006, 5, 660; (h) Rotella, D. P. Nat. Rev. Drug Disc. 2002, 1, 674.
3. Soderling, S. H.; Bayuga, S. J.; Beavo, J. A. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
7071.
reaction, mouse PDE10 (BPS BioSciences, CA) was added to
a final
concentration of 25 ng/ml. The reaction was incubated at 30 °C for 20 min.
PDE10 hydrolysis was terminated by the addition of yttrium silicate beads (GE
Healthcare, RPNQ0150) and counted on
a Wallac Microbeta scintillation
counter 1–2 h following the addition of the beads. Data was analyzed using
XLfit (Microsoft) from which IC50 values were obtained.
4. Fujishige, K.; Kotera, J.; Michibata, H.; Yuasa, K.; Takebayashi, S.; Okumura, K.;
Omori, K. J. Biol. Chem. 1999, 274, 18438.
5. Loughney, K.; Snyder, P. B.; Uher, L.; Rosman, G. J.; Ferguson, K.; Florio, V. A.
Gene 1999, 234, 109.
12. The inhibition of other PDE enzymes by the PDE10A inhibitors was evaluated
under the same conditions described above for PDE10A. Fractional inhibition
was evaluated at four concentrations (0.1, 1, 10, and 100 lM). In cases where
inhibition at the highest concentration was less than 50%, the lower limit value
in the logistic model was fixed to 0% activity.
13. Wadenberg, M. L.; Hicks, P. B. Neurosci. Biobehav. Rev. 1999, 23, 851.
14. Gleason, S. D.; Shannon, H. E. Psychopharmacology (Berl) 1997, 129, 79.
6. Hebb, A. L.; Robertson, H. A. Curr. Opin. Pharm. 2007, 7, 86.
7. Chappie, T. A.; Humphrey, J. M.; Allen, M. P.; Estep, K. G.; Fox, C. B.; Lebel, L. A.;
Liras, S.; Marr, E. S.; Menniti, F. S.; Pandit, J.; Schmidt, C. J.; Tu, M.; Williams, R.
D.; Yang, F. V. J. Med. Chem. 2007, 50, 182.
8. Wang, H.; Liu, Y.; Hou, J.; Zheng, M.; Robinson, H.; Ke, H. PNAS 2007, 104, 5782.