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D. Guay et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5554–5558
Table 3
References and notes
In vitro and in vivo profiles of 3, 18 and 20
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3
18
20
(b) Soderling, S. H.; Beavo, J. A. Curr. Opin. Cell Biol 2000, 12, 174.
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GST-PDE4A248 (IC50, nM)
1.4
6.2
6.7
Whole blood TNF-a (IC50, nM)
Human
Squirrel monkey
161
11
50
123
7
50
59
178
23
66
hERG binding (IC50
,
lM)
CYP450 2C9 inhibition (IC50
,
lM)
61.0
41
Pharmacokineticsa—T1/2 (F)
Rat
Dog
4 h (95%)
5 h (55%)
4 h (33%)
3.0
10
270
1.5 h (87%)
2 h (100%)
4 h (33%)
3.7
2
530
69
84
2 h (98%)
2 h (100%)
5 h (38%)
5.1
2
220
65
84
Squirrel monkey
Emesisb Cmax
(lM)
Dose (mg/kg)
Ratio (Cmax/IC50
)
Guinea pigc (% inhibition)
Sheepd (%inhibition)
53
92
a
Half-life (T1/2) and bioavailability (F) determined following po and iv adminis-
tration of test compound.
b
In a dose ranging study (rising dose po), the maximal drug plasma level mea-
sured after the first episode of emesis in at least one animal (n > 2). See Ref. 17.
Mean % inhibition of the ovalbumin-induced bronchoconstriction in conscious
guinea pigs dosed 0.03 mg/kg ip 30 min prior to challenge (n > 5). See Ref. 5d.
8. Friesen, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.; Côté, B.; Frenette,
R.; Girard, M.; Guay, D.; Huang, Z.; Jones, T. R.; Laliberté, F.; Lynch, J. J.; Mancini,
J.; Martins, E.; Masson, P.; Muise, E.; Pon, D. J.; Siegl, P. K. S.; Styhler, A.; Tsou, N.
N.; Turner, M. J.; Young, R. N.; Girard, Y. J. Med. Chem. 2003, 46, 2413. and
references cited therein.
c
d
Mean % inhibition of the late-phase Ascaris-induced bronchoconstriction in
9. Macdonald, D.; Mastracchio, A.; Perrier, H.; Dubé, D.; Gallant, M. l.; Lacombe, P.;
Deschênes, D.; Roy, B.; Scheigetz, J.; Bateman, K.; Li, C.; Trimble, L. A.; Day, S.;
Chauret, N.; Nicoll-Griffith, D. A.; Silva, J. M.; Huang, Z.; Laliberté, F.; Liu, S.;
Ethier, D.; Pon, D.; Muise, E.; Boulet, L.; Chan, C. C.; Styhler, A.; Charleson, S.;
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12. Chu, D. T. W.; Fernandez, P. B.; Claiborne, A. K.; Pihuleac, E.; Nordeen, C. W.;
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sheep dosed iv with 0.5 mg/(kg day) for 4 days and challenged 2 h post dose on day
4. See Ref. 18.
20 to have a low potential for causing emesis at therapeutic doses
as estimated by the high ratio of the emetic threshold Cmax over the
IC50 for inhibition of TNF-a in squirrel monkey whole blood (Table
3).
Finally, we evaluated the in vivo efficacy of these 1,8-naphthy-
ridinone derivatives in two models of asthma. Intraperitoneal
administration of either 18 or 20 produced potent and dose-depen-
dent inhibition of the ovalbumin-induced bronchoconstriction in
sensitized guinea pigs. Similarly, both compounds protected
against the late-phase bronchoconstrictor response to antigen
challenge in Ascaris-sensitive sheep following intravenous admin-
istration. Based on these overall profiles, 18 and 20 were selected
for further evaluation and considered as potential candidates for
development. Ultimately, compound 20 was chosen for clinical
development and identified as MK-0873. Results from phase I
studies are reported elsewhere.19
In summary, we have identified a series of 1-phenyl-1,8-naph-
thyridin-4-one-3-carboxamides as potent PDE4 inhibitors. A num-
ber of these compounds display reduced affinity for the hERG K+
channel and have low potential to prolong the QTc interval. Two
of these derivatives, 18 and 20, have good pharmacokinetic profiles
and were found to have low potential for causing emesis at thera-
peutic doses. This work led to the identification of MK-0873 for
clinical development as a potential new therapeutic agent for
chronic obstructive pulmonary disease and asthma.
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J.; Denker, A.; Miller, D.; van Doorn, M. B. A.; Shoemaker, R. C.; Cohen, A. F.;
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