2378
A. I. Sánchez et al. / Bioorg. Med. Chem. 21 (2013) 2370–2378
5. Paterniti, I.; Mazzon, E.; Gil, C.; Impellizzeri, D.; Palomo, V.; Redondo, M.; Perez,
D. I.; Esposito, E.; Martinez, A.; Cuzzocrea, S. PLoS One 2011, 6, e15937.
6. Giembycz, M. A.; Smith, S. J. Curr. Pharm. Des. 2006, 12, 3207.
7. Keravis, T.; Lugnier, C. Br. J. Pharmacol. 2012, 165, 1288.
8. Smith, S. J.; Cieslinski, L. B.; Newton, R.; Donnelly, L. E.; Fenwick, P. S.;
Nicholson, A. G.; Barnes, P. J.; Barnette, M. S.; Giembycz, M. A. Mol. Pharmacol.
2004, 66, 1679.
ture for 6 h. Afterwards the reaction was acidified with 1 N HCl (pH
3) and the solid formed was filtered off, washed with hexane and
dried under vacuum. The crystalline product obtained was recrys-
tallised from methanol.
4.1.12.1. 4-(2-Isopropyl-quinazolin-4-ylsulfanylmethyl)-biphe-
9. Lee, R.; Wolda, S.; Moon, E.; Esselstyn, J.; Hertel, C.; Lerner, A. Cell. Signal. 2002,
14, 277.
nyl-2-carboxylic acid (4k).
226ꢀ228 °C. IR (KBr): 3431, 1971, 1694, 1567, 1486, 1306, 1134,
761, 641 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 1.42 (6H, d,
White solid. Yield: 72%. Mp
10. Kadoshima-Yamaoka, K.; Murakawa, M.; Goto, M.; Tanaka, Y.; Inoue, H.;
Murafuji, H.; Nagahira, A.; Hayashi, Y.; Nagahira, K.; Miura, K.; Nakatsuka, T.;
Chamoto, K.; Fukuda, Y.; Nishimura, T. Immunol. Lett. 2009, 122, 193.
11. Vergne, F.; Bernardelli, P.; Lorthiois, E.; Pham, N.; Proust, E.; Oliveira, C.;
Mafroud, A.-K.; Ducrot, P.; Wrigglesworth, R.; Berlioz-Seux, F.; Coleon, F.;
Chevalier, E.; Moreau, F.; Idrissi, M.; Tertre, A.; Descours, A.; Berna, P.; Li, M.
Bioorg. Med. Chem. Lett. 2004, 14, 4615.
12. (a) Redondo, M.; Brea, J.; Perez, D. I.; Soteras, I.; Val, C.; Perez, C.; Morales-
Garcia, J. A.; Alonso-Gil, S.; Paul-Fernandez, N.; Martin-Alvarez, R.; Cadavid, M.
I.; Loza, M. I.; Perez-Castillo, A.; Mengod, G.; Campillo, N. E.; Martinez, A.; Gil, C.
J. Med. Chem. 2012, 55, 3274; (b) Morales-Garcia, J.; Redondo, M.; Gil, C.;
Alonso-Gil, S.; Martinez, A.; Santos, A.; Perez-Castillo, A. PLoS One 2011, 6,
e17240; (c) Gil, C.; Campillo, N. E.; Perez, D. I.; Martinez, A. Expert Opin. Ther.
Pat. 2008, 18, 1127.
13. (a) Goto, M.; Kadoshima-Yamaoka, K.; Murakawa, M.; Yoshioka, R.; Tanaka, Y.;
Inoue, H.; Murafuji, H.; Kanki, S.; Hayashi, Y.; Nagahira, K.; Ogata, A.;
Nakatsuka, T.; Fukuda, Y. Eur. J. Pharmacol. 2010, 633, 93; (b) Kadoshima-
Yamaoka, K.; Goto, M.; Murakawa, M.; Yoshioka, R.; Tanaka, Y.; Inoue, H.;
Murafuji, H.; Kanki, S.; Hayashi, Y.; Nagahira, K.; Ogata, A.; Nakatsuka, T.;
Fukuda, Y. Eur. J. Pharmacol. 2009, 613, 163.
.
J = 6.7 Hz), 3.28 (1H, hep, J = 6.7 Hz), 4.73 (2H, s), 7.26ꢀ7.35 (4H,
m), 7.40ꢀ7.52 (4H, m), 7.55ꢀ7.84 (2H, m), 7.94 (1H, d,
J = 7.8 Hz), 8.05 (1H, d, J = 8.6 Hz). Anal. Calcd for C25H22N2O2S: C,
72.44; H, 5.35; N, 6.76. Found: C, 72.82; H, 5.54; N, 6.56.
4.1.12.2. 4-(2-Isopropyl-quinazolin-4-ylsulfanylmethyl)-biphe-
nyl-3-carboxylic acid (4l).
165 °C. IR (KBr): 3414, 2965, 2925, 1694, 1564, 1303, 1236,
760 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 1.47 (6H, d, J = 6.8 Hz),
White solid. Yield: 69%. Mp 163–
.
3.33 (1H, hep, J = 6.8 Hz), 4.74 (2H, s), 7.48-7.57 (2H, m), 7.58–
7.61 (4H, m), 7.77–7.84 (2H, m), 7.98 (1H, d, J = 8.4 Hz), 8.04 (1H,
d, J = 8.3 Hz), 8.11 (1H, d, J = 7.9 Hz), 8.36 (1H, s). Anal. Calcd for
C25H22N2O2S: C, 72.44; H, 5.35; N, 6.76. Found: C, 72.82; H, 5.56;
14. Castano, T.; Wang, H.; Campillo, N. E.; Ballester, S.; Gonzalez-Garcia, C.;
Hernandez, J.; Perez, C.; Cuenca, J.; Perez-Castillo, A.; Martinez, A.; Huertas, O.;
Gelpi, J. L.; Luque, F. J.; Ke, H.; Gil, C. ChemMedChem 2009, 4, 866.
15. (a) Castro, A.; Abasolo, M. I.; Gil, C.; Segarra, V.; Martinez, A. Eur. J. Med. Chem.
2001, 36, 333; (b) Martinez, A.; Castro, A.; Gil, C.; Miralpeix, M.; Segarra, V.;
Domenech, T.; Beleta, J.; Palacios, J. M.; Ryder, H.; Miro, X.; Bonet, C.;
Casacuberta, J.; Azorin, F.; Pina, B.; Puigdomenech, P. J. Med. Chem. 2000, 43,
683.
16. Segarra, V.; Crespo, M. I.; Pujol, F.; Beleta, J.; Domenech, T.; Miralpeix, M.;
Palacios, J. M.; Castro, A.; Martinez, A. Bioorg. Med. Chem. Lett. 1998, 8, 505.
17. García, G.; Rodríguez-Puyol, M.; Alajarín, R.; Serrano, I.; Sánchez-Alonso, P.;
Griera, M.; Vaquero, J. J.; Rodríguez-Puyol, D.; Álvarez-Builla, J.; Díez-Marqués,
M. L. J. Med. Chem. 2009, 52, 7220.
N, 6.53.
4.1.12.3. 4-(2-Isopropyl-quinazolin-4-ylsulfanylmethyl)-biphe-
nyl-4-carboxylic acid (4m).
221–223 °C. IR (KBr): 3414, 2965, 1694, 1564, 1303, 1236,
760 cmꢀ1 1H NMR (300 MHz, CDCl3) d: 1.45 (6H, d, J = 6.9 Hz),
3.43 (1H, hep, J = 6.9 Hz), 4.73 (2H, s), 7.53ꢀ7.68 (7H, m), 7.84
(1H, t, J = 7.1 Hz), 7.99ꢀ8.06 (2H, m), 8.15 (2H, d, J = 8.4 Hz). Anal.
Calcd for C25H22N2O2S: C, 72.44; H, 5.35; N, 6.76. Found: C, 72.66;
H, 5.30; N, 6.87.
White solid. Yield: 89%. Mp
.
18. Delgado, F.; Pastor, J.; García-Navío, J. L.; Vaquero, J. J.; Alvarez-Buílla, J.;
Sunkel, C.; Casa-Juana, M. F.; Priego, J. G.; Santos, L. R.; Statkow, P. R.;
Straumann, D. Farmaco 1997, 52, 147.
4.2. Phosphodiesterase inhibition assay
19. Yde, B.; Yousif, N. M.; Pedersen, U.; Thomsen, I.; Lawesson, S. O. Tetrahedron
1984, 40, 2047.
20. Manhas, M. S.; Hoffman, W. A., III; Bose, A. K. J. Heterocycl. Chem. 1979, 16, 711–
715.
21. Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.;
Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S. E.;
Timmermans, P. B. M. W. M. J. Med. Chem. 1991, 34, 2525.
22. Carini, D. J.; Duncia, J. V.; Johnson, A. L.; Chiu, A. T.; Price, W. A.; Wong, P. C.;
Timmermans, P. B. M. W. J. Med. Chem. 1990, 33, 1330.
Compounds 1–4 are resuspended in DMSO at a stock concentra-
tion of 10 mM. The compounds are tested at concentrations rang-
ing from 1 mM to 1 nM in order to calculate an IC50. All dilutions
are performed in 96 well plates.
For each reaction 10
l
L of the diluted compounds are poured
L of a reaction mixture contain-
into ‘low binding’ assay plates. 80
l
ing 50 mM Tris pH 7.5, 8.3 mM MgCl2, 1.7 mM EGTA, and 15 nM
23. Santhosh, K. C.; Paul, G. C.; De Clercq, E.; Pannecouque, C.; Witvrouw, M.;
Loftus, T. L.; Turpin, J. A.; Buckheit, R. W., Jr.; Cushman, M. J. Med. Chem. 2001,
44, 703.
24. Keppler, A. F.; Sacurai, S. L.; Zaim, M. H.; Touzarim, C. E. C. PCT Int. Appl.
WO2011022798 A1 20110303, 2011.
30,50 [3H]-cAMP (around 150,000 dpm) are added to each well.
The reaction is initiated by adding 10 lL of a solution containing
PDE7 to the reaction mixture. The plate is then incubated under
25. (a) Kikuchi, K.; Watanabe, T.; Okazaki, T.; Yanagisawa, I.; Inagaki, O. Jpn. Kokai
Tokkyo Koho JP 06279437 A 19941004, 1994.; (b) Levin, J. I.; Venkatesan, A. M.
U.S. US 5286729 A 19940215, 1994.
26. Ueda, M.; Saitoh, A.; Oh-Tani, S.; Miyaura, N. Tetrahedron 1998, 54, 13079.
27. (a) Kikelj, D. Sci. Synth. 2004, 16, 573; (b) Yun, L. M.; Yangibaev, S.;
Shakhidoyatov, Kh. M.; Alekseeva, V. A.; V’yunov, K. A. Khim. Getero. Soedin.
1987, 254.
stirring for 1 h at room temperature. After incubation the reaction
is stopped with 50 lL (0.89 mg) of PDE SPA beads (Amersham
Pharmacia Biotech RPNQ0150), and the resulting mixture is al-
lowed to settle for 20 min before counting in a microlitre plate
counter.
28. Lempert-Sreter, M.; Lempert, K. Acta Chim. Hung. 1984, 117, 121.
29. (a) Chern, J. W.; Tao, P. L.; Yen, M. H.; Lu, G. Y.; Shiau, C. Y.; Lai, Y. J.; Chien, S. L.;
Chan, C. H. J. Med. Chem. 1993, 36, 2196; (b) Yale, H. L. J. Am. Chem. Soc. 1953,
75, 675.
30. Leonard, N. J.; Curtin, D. Y. J. Org. Chem. 1946, 11, 349.
31. Tomisek, A. J.; Christensen, B. E. J. Am. Chem. Soc. 1948, 70, 2423.
32. (a) El-Hiti, G. A. Synthesis 2004, 363; (b) Cohen, V. I. J. Heterocycl. Chem. 1978,
15, 1415.
Acknowledgements
This research was supported by Almirall Prodesfarma S.A.
Authors gratefully acknowledge financial support and Grants (A.
S. B and V. M.)
33. (a) Hanusek, J.; Hejtmankova, L.; Kubicova, L.; Sedlak, M. Molecules 2001, 6,
323; (b) Legrand, L.; Lozac´h, N. Bull. Soc. Chim. Fr. 1961, 618.
34. Connolly, D. J.; Lacey, P. M.; McCarthy, M.; Saunders, C. P.; Carroll, A.-M.;
Goddard, R.; Guiry, P. J. J. Org. Chem. 2004, 69, 6572.
35. (a) Zhou, J.; Fang, J. J. Org. Chem. 2011, 76, 7730; (b) Zentmyer, D. T.; Wagner, E.
C. J. Org. Chem. 1949, 14, 967.
References and notes
1. (a) Sutherland, E. W.; Rall, T. W. J. Biol. Chem. 1958, 232, 1077; (b) Sutherland, E.
W.; Rall, T. W. J. Am. Chem. Soc. 1957, 79, 3608.
2. Essayan, D. M. Biochem. Pharmacol. 1999, 57, 965.
36. Terakado, M.; Nakade, S.; Seko, T.; Takaoka, Y. PCT Int. Appl. WO2004031118
A1 20040415, 2004.
3. Lugnier, C. Pharmacol. Ther. 2006, 109, 366.
4. Redondo, M.; Zarruk, J. G.; Ceballos, P.; Perez, D. I.; Perez, C.; Perez-Castillo, A.;
Moro, M. A.; Brea, J.; Val, C.; Cadavid, M. I.; Loza, M. I.; Campillo, N. E.; Martínez,
A.; Gil, C. Eur. J. Med. Chem. 2012, 47, 175.