1236
L. C. Cooper et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1233–1236
pounds were subject to first pass metabolism. For 6e,
this strengthened the hypothesis drawn from the gerbil
results.
In conclusion, we have explored the effect of substitu-
tion on the core of a new series of high affinity NK1
antagonists based on 2-aryl indoles. We have shown
that 5-substitution is critical for good NK1 receptor
binding but that there is considerable tolerance for dif-
ferent 5-substituents, provided that they are small.
These compounds have high binding affinity and brain
penetration but are compromised by poor oral absorp-
tion. Introduction of a second nitrogen into the 6- and
7-positions of the indole nucleus is well tolerated. These
compounds have high binding affinity and good central
activity, with improved absorption, but high first pass
metabolism limits oral bioavailability.
Scheme 7. Reagents: (i) I2, AgSO4, EtOH (rt, 24 h); (ii) methyl 5-(40-
chlorophenyl)pent-4-ynoate, Pd(OAc)2, LiCl, Na2CO3, DMF (70 ꢂC,
.
24 h, 20–25%); (iii) NaH, MeI, DMF; (iv) LiOH H2O, MeOH, H2O;
(v) 4-benzyl-4-hydroxypiperidine, 1-hydroxybenzotriazole, Et3N,
EDC, THF (rt, 16 h); (vi) (BOC)2O, 1,4-dioxane (reflux, 18 h, 94%);
(vii) BuLi, I2, TMEDA, Et2O (ꢀ78 to ꢀ10 ꢂC, 18 h, 55%); (viii) TFA,
DCM.
Acknowledgements
The authors thank the combinatorial chemistry team at
our Rahway laboratory for developing the solid-phase
method that was used in this paper.4,9
A Vilsmeier formylation followed by a Wadsworth–
Emmons reaction and subsequent standard hydrolysis,
coupling and finally reduction gave 6a (Scheme 6).
Compounds 6b–e were made from iodination of the
corresponding amino-pyridines followed by palladium-
catalysed coupling18 with methyl 5-(40-chlorophenyl)-
pent-4-ynoate; standard methylation, hydrolysis and
coupling gave the target compounds (Scheme 7).
References and Notes
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The in vitro NK1 binding results for the azaindoles are
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Pharmacokinetic studies conducted in portal vein can-
nulated rats on 4a and 6e gave hepatic portal AUCs of
.
.
24.7 ng/mL h for 4a compared with 96.8 ng/mL h for 6e
.
and the systemic AUCs were <4 ng/mL h for 4a com-
.
pared with 8 ng/mL h for 6e. The almost 4-fold increase
in hepatic portal vein levels suggests that the azaindole
was more efficiently absorbed, as had been hoped, but
the fact that it did not have significantly improved sys-
temic levels compared to 4a shows that both com-