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life observed upon oral administration in both rats and
dogs.
References and notes
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Figure 2. Compound 20 bound to DPP-4. The overlay of compound
20 (yellow) and 2a (green, 2FJP.pdb) shows the different orientation of
the two compounds. Interactions of compound 20 with DPP-4 are
shown as red dotted lines. The hydrogen-bond network present
between the ordered water molecules, compound 20, and protein
atoms has been omitted for clarity.
4. (a) Xu, J.; OK, H. O.; Gonzalez, E. J.; Colwell, L. F.;
Habulihaz, B.; He, H.; Leiting, B.; Lyons, K.; Marsilio, F.;
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pound 43 displayed moderate oral bioavailability in rats
(F = 36%) and excellent oral bioavailability in dogs
(F = 95%). Unfortunately, 43 exhibited a short half-life
in both rats (t1/2 = 1.3 h) and dogs (t1/2 = 1.75 h).
Co-crystallization of 20 with the DPP-4 enzyme indi-
cates that the major interactions of compound 20 with
DPP-4 are similar to those observed with the Val-Pro
and Diprotin A substrate analogs and several other clas-
ses of inhibitors reported to date (Fig. 2).14 The pyrrol-
idine moiety is located in the P-1 site, adjacent to the
catalytic Ser630. The a-amino acid group forms four
hydrogen-bond interactions with the side chains of
Glu205, Glu206, Tyr662, and Asn710. The major differ-
ence between the binding mode of compound 20 and
that of other amino-acid derived compounds such as 2
is that it does not extend across the binding site to inter-
act with Arg358. The methylsulfonylphenyl ring stacks
against the side chain of Tyr547, and the methylsulfonyl
group extends toward a polar surface in an area of the
binding site that has not been utilized by any previously
reported compounds, although aminomethylpyrimi-
dines have been shown to extend in the same general
direction.14h The stereochemistry at the b-position is
critical for the binding potency, since the corresponding
anti-diastereoisomer is typically 10-fold less potent than
the syn-diastereoisomer in this series. The difference in
binding modes accounts for the switch in stereochemical
preference observed in this series (syn over anti) relative
to the biaryl derivatives 1 and 2.
10. For assay conditions for DPP-4 and QPP inhibition, see:
(a) Leiting, B.; Pryor, K. D.; Wu, J. K.; Marsilio, F.; Patel,
R. A.; Craik, C. S.; Ellman, J. A.; Cummings, R. T.;
Thornberry, N. A. Biochem. J. 2003, 371, 525; (b) All
multiple determinations of the IC50 values were within 1.5-
fold of the reported average.
11. Lankas, G. R.; Leiting, B.; Sinha Roy, R.; Eiermann, G.
J.; Beconi, M. G.; Biftu, T.; Chan, C.-C.; Edmondson, S.;
Feeney, W. P.; He, H.; Ippolito, D. E.; Kim, D.; Lyons, K.
A.; Ok, H. O.; Patel, R. A.; Petrov, A. N.; Pryor, K. A.;
In summary, we have discovered a novel series of po-
tent, selective, and orally bioavailable DPP-4 inhibitors.
These are among the most potent compounds reported
to date lacking an electrophilic trap. The optimized
compound 43 exhibited excellent selectivity over a vari-
ety of DPP-4 homologs. However, further development
of this compound was not pursued due to the short half-