A. K. Chatterjee et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2899–2903
2903
Immunity 1996, 4, 357; (b) Driessen, C.; Bryant, R. A.
´
addition, electron-donating substituents such as p-meth-
oxy analog 34 or a small aliphatic group analog 35 re-
duce Cat S potency, without any improvement in oral
exposure (Table 1). We found that a strong electron-
withdrawing group, such as a trifluoromethyl group 36,
retains Cat S potency while improving selectivity on
Cat K and L. The CF3 group must reside in the para-po-
sition as demonstrated by inactive isomers 37 and 38.
The isopropyl P1 group has a dramatic effect on Cat S
potency as an alanine derived P1 39 loses 100-fold po-
tency and cyclization of the P1 isopropyl group to cyclo-
propyl derivative 40 also significantly diminishes Cat S
activity. Complete removal of the P1 substituent (41) re-
duces Cat S inhibition by 1000-fold. In addition to
favorable hydrophobic interactions in the S1 pocket,
the P1 isopropyl group may also be playing a key role
in the conformation of the P2 phenylsuccinamide group
and its subsequent trajectory into the P2 pocket.16 We
were pleased to find that 36 displayed a 2-fold improve-
ment in the AUC as compared to 31. Analog 36 was la-
ter determined to have a modest oral bioavailability of
34% and represents a ꢀ100-fold improvement in AUC
when compared to lead compound 3.
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In conclusion, the use of a succinic acid backbone in
non-covalent cathepsin S inhibitors provided a novel
set of potent and selective compounds. The replacement
of the cyclohexyl P2 moiety with a substituted phenyl
group ring improved the selectivity profile and oral
exposure, as demonstrated by analog 36. The use of a
‘rapid-rat’ protocol allowed for testing a wider variety
of analogs to address the low oral exposure of the early
compounds and allowed for the parallel optimization of
potency, selectivity, and oral exposure.
Acknowledgments
The authors acknowledge Mike Hornsby for protein
production. The authors also thank Terry Hart and
Allan Hallett (Novartis Institutes for Biomedical
Research) for valuable discussions.
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