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potency was observed in the dihydroxy compound 49
(Ki = 14 nM). As was noted for the nitrile-containing
series, a strong stereochemical preference was main-
tained for the methano bridge bearing the 2S,3R-config-
uration (compare 43 with 44 and 48 with 50). The
apparently unique potency enhancing properties of this
bulky P2 unit are further demonstrated with simple pyr-
rolidine (51) and thiazolidine (53) P1 groups, though the
3- to 5-fold diminished potency compared with 48 serve
to validate the role of the methano bridge in this precise
regio- and stereochemical orientation (compare with 57)
in favorably contributing to DPP-IV binding affinity. It
is noteworthy that strict steric constraints exist in the S1
pocket, such that even simple methyl substitution as in
54 essentially destroys all activity. The most potent com-
pound in the series was obtained by packing further
bulk into the S2 pocket (58, Ki = 2.9 nM), though a
change as subtle as opening the bicyclic methanopyrroli-
dine to a piperidine (59) results in a 200-fold drop in po-
tency. Interestingly, methanopyrrolidine analogues with
N-linked substitution analogous to vildagliptin (60)
failed to demonstrate any significant DPP-IV inhibitory
activity.
3. Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.; Burkey,
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M.; Munetomo, E.; Kitano, K.; Saito, H.; Takaoka, Y.;
Yamamoto, K. Bioorg. Med. Chem. 2004, 12, 6053; (b)
Haffner, C. D.; McDougald, D. L.; Reister, S. M.;
Thompson, B. D.; Conlee, C.; Fang, J.; Bass, J.; Lenhard,
J. M.; Croom, D.; Secosky-Chang, M. B.; Tomaszek, T.;
McConn, D.; Wells-Knecht, K.; Johnson, P. R. Bioorg.
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13. Madar, D. J.; Kopecka, H.; Pireh, D.; Yong, H.; Pei, Z.;
Li, X.; Wiedeman, P. E.; Djuric, S. W.; Von Geldern, T.
W.; Fickes, M. G.; Bhagavatula, L.; McDermott, T.;
Wittenberger, S.; Richards, S. J.; Longenecker, K. L.;
Stewart, K. D.; Lubben, T. H.; Ballaron, S. J.; Stashko,
M. A.; Long, M. A.; Wells, H.; Zinker, B. A.; Mika, A.
K.; Beno, D. W.; Kempf-Grote, A. J.; Polakowski, J.;
Segreti, J.; Reinhart, G. A.; Fryer, R. M.; Sham, H. L.;
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The unique structural features imparted to inhibitors by
the hydroxyadamantylglycine P2 group appear to be
capable of conferring significant potency to non-nitrile
compounds, though limited by the same narrow steric
and stereochemical requirements shown for nitrile-con-
taining inhibitors. Interestingly, several of the more po-
tent analogues in this series have retained some slow
binding kinetic properties, despite the lack of a nitrile
(dissociation rate increases from 4.6 · 10À5/s for saxag-
liptin to 2.0 · 10À3/s for compound 48 at 25 ꢁC, unpub-
lished results). Compound 48 maintains potent and fully
efficacious antihyperglycemic effects in rodent models
and mirrors the PK and safety profiles of clinical lead
compound saxagliptin, yet is incapable of undergoing
degradative cyclization. As previously discussed, this
inhibitor also shows uniquely potent inhibition relative
to other non-cyano compounds, suggesting that the
summation of contributions to the binding energy of
this compound in the active site is largely dominated
by the P2 hydroxyadamantylglycine moiety. These stud-
ies have shown the development of chemically more sta-
ble and potent DPP-IV inhibitors in the low nM range,
specifically compounds 48, 49 and 58. Further studies
examining in vivo pharmacological effects as well as bio-
chemical and biophysical aspects of the binding interac-
tions for these potent compounds will be the subject of
forthcoming disclosures from these laboratories.
15. Magnin, D. R.; Robl, J. A.; Sulsky, R. B.; Augeri, D. J.;
Huang, Y.; Simpkins, L. M.; Taunk, P. C.; Betebenner, D.
A.; Robertson, J. G.; Abboa-Offei, B.; Wang, A.; Cap, M.;
Xin, L.; Tao, L.; Sitkoff, D. F.; Malley, M. F.; Gougoutas,
J. Z.; Khanna, A.; Huang, Q.; Han, S.-P.; Parker, R. A.;
Hamann, L. G. J. Med. Chem. 2004, 47, 2587.
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