Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 7, 2007, Pages 2005-2012

  Backes, Bradley J ^a   Longenecker, Kenton ^a   Hamilton, Gregory L ^a   Stewart, Kent ^a   Lai, Chunqiu ^a   Kopecka, Hana ^a   von Geldern, Thomas W ^a   Madar, David J ^a   Pei, Zhonghua ^a   Lubben, Thomas H ^a   Zinker, Bradley A ^a   Tian, Zhenping ^a   Ballaron, Stephen J ^a   Stashko, Michael A ^a   Mika, Amanda K ^a   Beno, David W A ^a   Kempf Grote, Anita J ^a   Black Schaefer, Candace ^a   Sham, Hing L ^a   Trevillyan, James M ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

Diabetes; DPPIV inhibitors; Structure based design

Indexed keywords

CYCLOHEXENE DERIVATIVE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; PHENETHYLAMINE DERIVATIVE; PYRROLIDINE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; FEMALE; GLUCOSE BLOOD LEVEL; HUMAN; HUMAN CELL; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PROTEIN STRUCTURE; RAT; SCREENING;

ANIMALS; ANTIGENS, CD26; BLOOD GLUCOSE; CHEMISTRY, PHARMACEUTICAL; CYCLOHEXENES; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; ENZYME INHIBITORS; FEMALE; HYPOGLYCEMIC AGENTS; MODELS, CHEMICAL; MOLECULAR CONFORMATION; PHENETHYLAMINES; PYRROLIDINES; RATS;

RATTUS;

EID: 33847628449     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.01.026     Document Type: Article

References (39)

1. Zander M., Madsbad S., Madsen J.L., and Holst J.J. Lancet 359 (2002) 824
2. Diabetologia 35 (1992) 701
3. For reviews see:. Holst J.J. Gastroenterology 107 (1994) 1048
4. Drucker D.J. Diabetes 47 (1998) 159
5. Deacon C.F., Holst J.J., and Carr R.D. Drugs Today 35 (1999) 159
6. Wettergren A., Schjoldager B., Mortensen P.E., Myhre J., Christiansen J., and Holst J.J. Dig. Dis. Sci. 38 (1993) 665
7. Nauck M.A., Niedereichholz U., Ettler R., Holst J.J., Orskov C., Ritzel R., and Schmiegel W.H. Am. J. Physiol. 273 (1997) E981
8. Flint A., Raben A., Ersboll A.K., Holst J.J., and Astrup A. Int. J. Obes. 25 (2001) 781
9. Farilla L., Hui H., Bertolotto C., Kang E., Bulotta A., Di Mario U., and Perfetti R. Endocrinology 143 (2002) 4397
10. Kieffer T.J., McIntosh C.H.S., and Pederson T.A. Endocrinology 136 (1995) 3585
11. Deacon C.F., Nauck M.A., Toft-Nielson M., Pridal L., Willms B., and Holst J.J. Diabetes 44 (1995) 1126
12. Ahrén B., Simonsson E., Larsson H., Landin-Olsson M., Torgeirsson H., Jansson P.-A., Sandqvist M., Bavenholm P., Efendic S., Eriksson J.W., Dickinson S., and Holmes D. Diabetes Care 25 (2002) 869
13. Ahrén B., Gomis R., Standl E., Mills D., and Schweizer A. Diabetes Care 27 (2004) 2874
14. Ahrén B., Landing-Olsson L., Jansson P.-A., Sevensson M., Holmes D., and Schweizer A. J Clin. Endocrinol. Metab. 89 (2004) 2078
15. Ahrén B., Pacini G., Foley J.E., and Schweizer A. Diabetes Care 28 (2005) 1936
16. Villhauer E.B., Brinkman J.A., Naderi G.B., Burkey B.F., Dunning B.E., Prasad K., Mangold B.L., Russell M.E., and Hughes T.E. J. Med. Chem. 46 (2003) 2774
17. 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.E., Patel R.A., Petrov A., Scapin G., Patel S.B., Sinha Roy R., Wu J.K., Wyvratt M.J., Zhang B.B., Zhu L., Thornberry N.A., and Weber A.E. J. Med. Chem. 48 (2005) 141
18. Augeri D.J., Robl J.A., Betebenner D.A., Magnin D.R., Khanna A., Robertson J.G., Wang A., Simpkins L.M., Taunk P., Huang Q., Han S.-P., Abboa-Offei B., Cap M., Xin L., Tao L., Tozzo E., Welzel G.E., Egan D.M., Marcinkeviciene J., Chang S.Y., Biller S.A., Kirby M.S., Parker R.A., and Hamann L.G. J. Med. Chem. 48 (2005) 5025
19. 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.A., Kempf-Grote A.J., Polakowski J., Segreti J., Reinhart G.A., Fryer R.M., Sham H.L., and Trevillyan J.M. J. Med. Chem. 49 (2006) 6416
20. Oprea T.I., Davis A.M., Teague S.J., and Leeson P.D. J. Chem. Inf. Comput. Sci. 41 (2001) 1308
21. Abad-Zapatero C., and Metz J.T. Drug Discovery Today 10 (2005) 464
22. Lead-like hit 5 has been optimized to provide a clinical candidate. Pei Z., Li X., von Geldern T.W., Madar D.J., Longenecker K., Yong H., Lubben T.H., Stewart K.D., Zinker B.A., Backes B.J., Judd A.S., Mulhern M., Ballaron S.J., Stashko M.A., Mika A.K., Beno D.W.A., Reinhart G.A., Fryer R.M., Preusser L.C., Kempf-Grote A.J., Sham H.L., and Trevillyan J.M. J. Med. Chem. 49 (2006) 6439
23. Padwa A., and Chen Y.Y. Tetrahedron Lett. 25 (1984) 5739
24. Jorand-Lebrun C., and Valognes D. Synth. Commun. 23 (1998) 1189
25. Cambell A.L., Pilipauskas D.R., Khanna I.K., and Rhodes R.A. Tetrahedron Lett. 28 (1987) 2331
26. Shute R.E., and Rich D.H. Synthesis (1987) 346
27. Hamilton G.L., and Backes B.J. Tetrahedron Lett. 47 (2006) 967
28. Luo G., Chen L., and Poindexter G.S. Tetrahedron Lett. 43 (2002) 5739
29. Hamilton G.L., and Backes B.J. Tetrahedron Lett. 47 (2006) 2229
30. A matrix of chiral acids (d-tartaric acid, d-malic acid, (1R)-(-)10-camphorsulfonic acid, and (R)-(-)-mandelic acid) and solvents (THF, EtOH, EtOAc and acetone) were evaluated to resolve 21c (±). The use of d-tartaric acid and EtOH provided a practical solution.
31. Shuai, Q.; Patel, J.; Zanze, I.; Dinges, J.; Wiedeman, P.; Pei, Z.; Michmerhuizen, M. J.; Hoff, E.; Kalvin, D. M.; von Geldern, T.; Lubben, T.; Ballaron, S.; Stashko, M.; Zinker, B.; Djuric, S.; Beno, D.; Kempf-Grote, A. J.; Mika, A.; Farb, T.; Perham, M. A.; Adler, A. L.; Trevillyan, J.; Sham H. Acyl thiazolidides-novel potent DPP-IV inhibitors, MEDI Poster 303, American Chemical Society National Meeting, Aug 28-Sep 1, 2005; Washington, DC, USA.
32. For initial studies, thiophene substitution was evaluated rather than thiazole substitution since the requisite starting material (thiophene boronic acid) is commercially available.
33. It is noteworthy that 2 (MK-0431) has an aryl group with a similar 2,4,5-trifluorosubstitution pattern as 25c. We obtained internal co-crystal structures using compounds similar to 2 (Edmondson, D. D.; Parmee, E.; Weber, A. E.; Xu, J. Dipeptidyl Peptidase Inhibitors for the Treatment of Diabetes, Patent WO 03/000180, January 3, 2003). The data indicated that our pyrrolidine-based inhibitors and the Merck inhibitors share a similar aryl binding mode. On that basis, compounds featuring the 2,4,5-trifluorosubstitution pattern were included in our SAR studies.
34. An X-ray crystal structure was obtained from d-tartaric acid salt 26. The stereochemical assignments of the pyrrolidine substituents of 26 were in agreement with protein crystal structure (Fig. 1d). These data further confirm the stereochemical assignment of 29b as the active enantiomer of 25c (±).
35. Abbott C.A., Yu D.M.T., Woollatt E., Sutherland G.R., McCaughan G.W., and Gorrell M.D. Eur. J. Biochem. 267 (2000) 6140
36. Ajami K., Abbott C.A., McCaughan G.W., and Gorrell M.D. Biochem. Biophys. Acta 1679 (2004) 18
37. Rosenblum J.S., and Kozarich J.W. Curr. Opin. Chem. Biol. 7 (2003) 496
38. Scanlan M.J., Raj B.K.M., Calvo B., Garin-Chesa P., Sanz-Moncasi M.P., Healey J.H., Old L.J., and Rettig W.J. Proc. Natl. Acad. Sci. U.S.A. 91 (1994) 5657
39. Lankas G.R., Leiting B., Roy R.S., 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., Qian X., Reigle L., Woods A., Wu J.K., Zaller D., Zhang Z., Zhu L., Weber A.E., and Thornberry N.A. Diabetes 54 (2005) 2988