F357 side chain electronically, but also electronically and
sterically with the Y585 side chain.
7 Cox, J. M.; Chu, H. D. PCT Int. Appl. WO2008060488 A1.
8 For R = CH3, Z = CH the ratio of 4 to 5 was assigned based on presumed
reaction mechanism where the NH2 reacts in a Michael fashion with the
enone preferentially versus 1,2-addition to the carbonyl: 4 1H NMR (500
MHz, CD3OD) = 8.46 (s, 1H), 6.56 (s, 1H), 4.55 (s, 2H), 4.36 (s, 2H), 2.52
(s, 3H); 5 1H NMR (500 MHz, CD3OD) = 8.78 (s, 1H), 6.42 (s, 1H), 4.52
(s, 2H), 4.33 (s, 2H), 2.46 (s, 3H). For R = CH3, Z = N the ratio of 4 to 6 was
assigned by the presumed reduced methyl steric environment of 4 versus 5 in
the reaction; 4 1H NMR (500 MHz, CD3OD) = 8.52 (s, 1H), 4.56 (s, 2H),
4.37 (s, 2H), 2.50 (s, 3H); 6 1H NMR (500 MHz, CD3OD) = 8.58 (s, 1H),
4.54 (s, 2H), 4.33 (s, 2H), 2.46 (s, 3H).
R12
E20
E20
R358
9 Synthesis of cyclohexanone: (a) Biftu, T.; Scapin, G.; Singh, S.; Feng, D.;
Becker, J. W.;Eiermann, G.; He, H.; Lyons, K.; Patell, S.; Petrov, A.; Sinha-
Roy, R.; Zhang, B.; Wu, J.; Zhang, X.; Doss, G. A.; Thornberry,
N. A.; Weber, A. E. Bioorg. Med. Chem. Lett. 2007, 17, 3384; (b) Gao, Y-G.;
Feng, D.; Sheridan, R. P.; Scapin, G.; Patel, S. B.; Wu, J. K.; Zhang, X.;
Sinha-Roy, R.; Thornberry, N. A.; Weber, A. E.; and Biftu, T. Bioorg. Med.
Chem. Lett. 2007, 17, 3877. Synthesis of pyranone: See reference 6 and Biftu,
T.; Roy, R. S.; Chen, P.; Qian, X.; Feng, D.; Kuethe, J. T.; Scapin, G.; Gao,
Y. D.; Yan, Y.; Krueger, D.; Bak, A.; Eiermann, G.; He, J.; Cox, J.; Hicks, J.;
Lyons, K.; He, H.; Salituro, G.; Tong, S.; Patel, S.; Doss, G.; Petrov, A.; Wu,
J.; Xu, S. S.; Sewall, C.; Zhang, X.; Zhang, B.; Thornberry, N. A.; Weber, A.
E. J. Med. Chem. 2014, 57, 3205.
S63
F35
Y54
Y585
10 All final compounds were characterized by 1H NMR and LC/MS.
11 Rosenblum, J. S.; Kozarich, J. W. Curr. Opin. Chem. Biol. 2003, 7, 1.
12 Abbot, C. A.; Yu, D. M.; Woollatt, E.; Sutherland, G. R.; McCaughan, G.
W.; Gorrell, M. D. Eur. J. Biochem. 2000, 267, 6140.
Figure 2. X-ray co-crystal structure of omarigliptin (2) in yellow and
compound 30 in green, bound in the DPP-4 active site. (PDB code:
omarigliptin 2 with DPP-4, 4PNZ; compound 30 with DPP-4, 5ISM).
13 Olsen, C.; Wagtmann, N. Gene 2002, 299, 185.
14 Scallan, M. J.; Raj, B. K. M.; Calvo, B.; Garin-Chesa, P.; Sanz-Moncasi,
M. P.; Healey, J. H.; Old, L. J.; Rettig, W. J. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 5657.
In summary, we discovered a novel series of 5,6,5- and 5,5,6-
tricyclic pyrrolidines that are potent and selective DPP-4
inhibitors. These efforts culminated in the synthesis of compound
45 which demonstrated exquisite DPP-4 potency (IC50 = 0.12
nM), selectivity (IC50 > 30000 nM) across all proteases, ion
channels (IC50 > 23000 nM) and CYPs (IC50 > 44000 nM) tested,
including proteases, ion channels and CYPs not shown.
Unfortunately, the PK profile of 45 was inferior to omarigliptin
and was not profiled further as a potential once weekly
medication to treat type 2 diabetes mellitus.
15 (a) Sedo, A.; Malik, R. Biochim. Biophys. Acta 2001, 1550, 107; (b)
Rosenblum, J. S.; Kozarich, J. W. Curr. Opin. Chem. Biol. 2003, 7, 496.
16 McDonald, J. K.; Leibach, F. H.; Grindeland, R. E.; Ellis, S. J. Biol. Chem.
1968, 243, 4143.
17 Cox, J. M.; Presented at the 33rd National Medicinal Chemistry
Symposium, Tucson, AZ, May 2012.
18 6,5,6-tricyclic piperazine derivatives were prepared and demonstrated
inferior DPP-4 potency (IC50 > 1000 nM) compared to the analogs described.
19 (a) IC50 determinations for hERG were carried out as described in Friesen,
R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.; Cote, B.; Frenette,
R.; Girard, M.; Guay, D.; Huang, Z.; Jones, T. R.; Laliberte, F.; Lynch, J. J.;
Mancini, J.; Martins, E.; Masson, P.; Muise, E.; Pon, D. J.; Siegel, P. K. S.;
Styhler, A.; Tsou, N. N.; Turner, M. J.; Young, R. N.; Girard, Y. J. Med.
Chem. 2003, 46, 2017. (b) IC50 determinations for rabbit calcium channel
were carried out as described in: Schoemaker, H.; Hicks, P.; Langer, S. J.
Cardiovasc. Pharm. 1987, 9, 173.
Acknowledgments
The authors thank Gina Black, Joe Leone, Daniel Kim, Elliot
Martel and Derek von Langen for large scale synthetic support
and Bernard Choi and Eric Streckfuss for analytical support.
20 (a) CYP3A4 and CYP2C9 potencies were evaluated and in all cases the
IC50 > 50 M. CYP2D6 was the only CYP with IC50 < 50 M. (b) Rendic, S.
Drug Metab. Rev. 2002, 34, 83.
References and notes
21 Omarigliptin demonstrated a superb dog PK profile: Cl = 0.9 (mL/min/kg);
t1/2 = 22 (h); Foral = ~100 %; nAUC = 54 (Mh/mg/kg) and see ref 5.
Allometric scaling suggested compound 45 would be suitable for QD dosing.
22 No in vivo PD efficacy studies were performed with analogs in the tricyclic
series. Based on Merck’s rich history in delivering potent and selective DPP-
4 inhibitors with superior PK, pharmacodynamics studies were reserved for
potential clinical candidates.
1 IDF Diabetes Atlas, 3rd ed.; International Diabetes Federation: Brussels,
2 (a) Holst, J. J. Diabetologia 2006, 49, 253; (b) Baggio, L. L.; Drucker, D. J.
Gastroenterology 2007, 132, 2131.
23 For greater discussion on crystal structures in the 5,5-series, see ref 5b and
9b.
3 (a) Holst, J. J.; Vilsboll, T.; Deacon, C. F. Mol.Cell. Endocrinol. 2009, 297,
127; (b) Brubaker, P. L. Endocrinology 2010, 151, 1984.
4 Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.; He, H.;
Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.; Marsilio, F.;
McCann, M.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel, S. B.; Sinha-Roy, R.;
Wu, J. K.; Wyvratt, M. J.; Shang, B. B.; Zhu, L.; Thornberry, N. A.; Weber,
A. E. J. Med. Chem. 2005, 48, 141, and references therein.
5 (a) Biftu, T.; Sinha-Roy, R.; Chen, P.; Qian, X.; Feng, D.; Kuethe, J. T.;
Scapin, G.; Gao, Y.-D.; Yan, Y.; Krueger, D.; Bak, A.; Eiermann, G.; He, J.;
Cox, J. M.; Hicks, J.; Lyons, K.; He, H.; Salituro, G.; Tong, S.; Patel, S.;
Doss, G.; Petrov, A.; Wu, J.; Xu, S.; Sewall, C.; Zhang, X.; Zhang, B.;
Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2014, 57, 3205. (b) Chen, P.;
Feng, D.; Qian, X.; Apgar, J.; Wilkening, R.; Kuethe, J. T.; Gao, Y.-D.;
Scapin, G.; Cox, J. M.; Doss, G.; Eiermann, G.; He, H.; Li, X.; Lyons, K. A.;
Metzger, J.; Petrov, A.; Wu, J. K.; Xu, S.; Weber, A. E.; Yan, Y.; Sinha-Roy,
R.; Biftu, T. Bioorg. Med. Chem. Lett. 2015, 25, 5767.
6
Biftu, T.; Qian, X.; Chen, P.; Feng, D.; Scapin, G.; Gao, Y. D.; Cox, J.;
Sinha-Roy, R.; Eiermann, G.; He, H.; Lyons, K.; Salituro, G.; Patel, S.;
Petrov, A.; Xu, F.; Xu, S. S.; Zhang, B.; Caldwell, C.; Wu, J. K.; Lyons, K.;
Weber, A. E. Bioorg. Med. Chem. Lett. 2013, 23, 5361.