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J. E. Stelmach et al. / Bioorg. Med. Chem. Lett. 13 (2003) 277–280
Table 4. p38a inhibition and rat pharmokinetic data for compound 15
Compd
R
p38a
IC50 (nM)
TNF-a cell
IC50 (nM)
TNF-a WB
IC50 (nM)
IV
t1/2 (h)
Vd
(L/kg)
Clp
(mL/min/kg)
AUCn PO
(mM h)
F
(%)
15a
15b
15c
15d
15e
15f
15g
15h
15i
Methyl
Ethyl
i-Propyl
0.5
1.2
0.6
1.1
0.5
0.3
0.4
0.6
0.2
1.3a
0.7b
0.2b
16.6a
0.3b
—
—
4.0
5.6
—
7.6
7.0
12.2
27.1
10.1
1.5
2.2
1.9
2.5
1.9
2.0
1.7
1.6
2.2
5.3
7.5
12.2
8.1
6.3
4.7
6.6
2.5
6.0
49.8
56.3
84.8
51.7
50.9
31.1
53.7
24.2
35.2
0.06
0.11
0.06
0.39
0.15
0.36
0.14
0.14
0.58
9.2
20.0
16.0
59.3
22.6
38.0
24.7
11.6
67.7
Cyclopropyl
Methyl Cyclopropyl
Ethyl 1-Cyclopropyl
Cyclobutyl
Methyl Cyclobutyl
t-butyl
0.5b
—
0.6b
aMonocyte cells.
bTHP-1 cells.
5. (a) Salituro, F. G. 11th RSC-SCI Medicinal Chemistry
Symposium, Churchill College, Cambridge, UK, Sept 9–12,
2001. (b) Bemis, G. W.; Salituro, F. G.; Duffy, J. P.; Cochran,
J. E.; Harrington, E. M.; Murcko, M. A.; Wilson, K. P.; Su,
M.; Galullo, V. P. Intl. Patent WO 98/27098, 1998.
6. Salituro, F. G. 27th National Medicinal Chemistry Sym-
posium, Kansas City, MO, June 13–17, 2000.
7. Natarajan, S. R.; Wisnoski, D. D.; Singh, S. B.; Stelmach,
J. E.; O’Neill, E. A.; Schwartz, C. D.; Thompson, C. M.;
Fitzgerald, C. E.; O’Keefe, S. J.; Kumar, S.; Hop, C. E. C. A;
Zaller, D. M.; Schmatz, D.M.; Doherty, J. B. Biorg. Med.
Chem. Lett. 2003, 13, 273
8. Liverton, N. J.; Butcher, J. W.; Claiborne, D. A.; Libby,
B. E.; Nguyen, K. T.; Pitzenberger, S. M.; Selnick, H. G.;
Smith, G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agarwal,
L.; Dancheck, K.; Forsyth, A. J.; Fletcher, D. S.; Frantz, B.;
Hanlon, W. A.; Harper, C. F.; Hofsess, S. J.; Kostura, M.;
Lin, J.; Luell, S.; O’Neill, E. A.; Orevillo, C. J.; Pang, M.;
Parsons, J.; Rolando, A.; Sahly, Y.; Visco, D. M.; O’Keefe,
S. J. J. Med. Chem. 1999, 42, 2180.
monocytes, THP-1 cells and human whole blood (WB).
Small N-alkyl substituents (i.e., methyl, ethyl, i-propyl,
15a–c) gave a modest improvement in rat PK.15 In
contrast, a bulky N-t-butyl substituent (15i) markedly
improved the rat PK (F=68%).
In summary, we have described the design and optimi-
zation of dihydroquinazolinone p38a inhibitors, which
can be considered hybrids of the pyridinylimidazole 1
and VX-745. Dihydroquinazolinone analogues posses-
sing a C-7 piperidine or piperazine moiety effectively
suppressed the production of TNF-a in monocyte cells,
THP-1 cells and whole blood. These analogues had high
clearance and low oral bioavailability in rats. However,
substitution of the piperidine nitrogen with a bulky
t-butyl substituent dramatically improved the clearance
and oral exposure in rats.
9. Human non activated p38a was purified and crystallized as
described by Wilson, K. P.; Fitzgibbon, M. J.; Caron, P. R.;
Griffith, J. P.; Chen, W.; McCaffrey, P. G.; Chambers, S. P.;
Su, M. J. Biol. Chem. 1996, 271, 27696. The complex was
obtained by soaking an apo crystal in 200 mM compound 14e
for 6 h. Additional details including coordinates can be found
at the Protein Data Bank, accession code 1M7Q.
References and Notes
1. (a) Bondeson, J.; Maini, R. N. Int. J. Clin. Pract. 2001, 55,
211. (b) Pugsley, M. K. Curr. Opin. Investig. Drugs 2001, 2,
1725.
2. Chen, Z.; Gibson, T. B.; Robinson, F.; Silvestro, L.; Pear-
son, G.; Xu, B.; Wright, A.; Vanderbilt, C.; Cobb, M. H.
Chem. Rev. 2001, 101, 2449.
10. Scapin, G. Keystone Symposia J1/J2, Breckenridge, CO,
Jan 5–11, 2002.
11. Yang, B. H.; Buchwald, S. L. Organ. Lett. 1999, 1, 5.
12. The copper mediated cyclizations of ureas 7 lacking the
internal PMB protecting group were not clean.
13. Palladium mediate coupling of 8 with 2,4-di-FlPhSSnBu3
gave 9s.
14. Analogue 15i was prepared via the Stille coupling of 12c
with the corresponding N-t-butyl analogue of 13.
15. HPLC/MS/MS analysis of 15c incubated with rat hepato-
cytes indicated oxidative N-dealkylation of the piperidine and
oxidation/conjugation of the C-5 phenyl and the C-4 benzylic
carbon proximal to the urea moiety.
3. Boehm, J. C.; Adams, J. L. Exp. Opin. Ther. Pat. 2000, 10,
25 and references therein.
4. (a) Tong, L.; Pav, S.; White, D. M.; Rogers, S.; Crane,
K. M.; Cywin, C. L.; Brown, M. L.; Pargellis, C. A. Nat.
Struct. Biol. 1997, 4, 311. (b) Wilson, K. P.; McCaffrey, P. G.;
Hsiao, K.; Pazhanisamy, S.; Galullo, V.; Bemis, G. W.; Fitz-
gibbon, M. J.; Caron, P. R.; Murcko, M. A.; Su, M. S. S.
Chem. Biol. 1997, 4, 423. (c) Wang, Z.; Canagarajah, B. J.;
Boehm, J. C.; Kassisa, S.; Cobb, M. H.; Young, P. R.; Abdel-
Meguid, S.; Adams, J. L.; Goldsmith, E. J. Structure 1998, 6,
1117.