4-Aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 10, 2007, Pages 2879-2885

  Duffy, Joseph L ^a   Kirk, Brian A ^a   Wang, Liping ^a   Eiermann, George J ^a   He, Huaibing ^a   Leiting, Barbara ^a   Lyons, Kathryn A ^a   Patel, Reshma A ^a   Patel, Sangita B ^a   Petrov, Alexsandr ^a   Scapin, Giovanna ^a   Wu, Joseph K ^a   Thornberry, Nancy A ^a   Weber, Ann E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Buchwald amidation; Dipeptidyl peptidase IV; DPP 4; Kazmaier Claisen; X ray

Indexed keywords

4 AMINOCYCLOHEXYLALANINE DERIVATIVE; 4 AMINOPHENYLALANINE DERIVATIVE; ALANINE DERIVATIVE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; PHENYLALANINE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; IC 50; LOW DRUG DOSE; NONHUMAN; RAT; X RAY ANALYSIS;

ADMINISTRATION, ORAL; ALANINE; ANIMALS; ANTIGENS, CD26; BINDING SITES; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; CYCLOHEXANES; ENZYME INHIBITORS; GLUCOSE TOLERANCE TEST; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PHENYLALANINE; STRUCTURE-ACTIVITY RELATIONSHIP;

MURINAE;

EID: 34247369404     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.02.066     Document Type: Article

References (25)

1. Gautier J.F., Fetita S., Sobngwi E., and Salaun-Marin C. Diabetes Metab. 31 (2005) 233
2. Holst J.J. Diabetologia 49 (2006) 253
3. Drucker D.J. Cell Metab. 3 (2006) 153
4. Zander M., Madsbad S., Madsen J.L., and Holst J.J. Lancet 359 (2002) 824
5. Deacon C.F., and Holst J.J. Int. J. Biochem. Cell Biol. 38 (2006) 831
6. Demuth H.-U., McIntosh C.H.S., and Pederson R.A. Biochim. Biophys. Acta 1751 (2005) 33
7. Augustyns K., Van der Veken P., and Haemers A. Expert Opin. Ther. Pat. 15 (2005) 1354
8. Weber A.E. J. Med. Chem. 47 (2004) 4135
9. Rosenblum J.S., and Kozarich J.W. Curr. Opinion Chem. Biol. 7 (2003) 496
10. Sedo A., and Malik R. Biochem. Biophys. Acta 1550 (2001) 107
11. Lankas G.R., Leiting B., Sinha Roy R., Eiermann G.J., Biftu T., Cahn C.-C., Edmondson S.D., 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 X., Zhu L., Weber A.E., and Thornberry N.A. Diabetes 54 (2005) 2988
12. Xu J., Wei L., Mathvink R., He J., Park Y.-J., He H., Leiting B., Lyons K.A., Marsilio F., Patel R.A., Wu J.K., Thornberry N.A., and Weber A.E. Bioorg. Med. Chem. Lett. 15 (2005) 2533
13. Edmondson S.D., Mastracchio A., Duffy J.L., Eiermann G.J., He H., Ita I., Leiting B., Leone J.F., Lyons K.A., Makarewicz A.M., Patel R.A., Petrov A., Wu J.K., Thornberry N.A., and Weber A.E. Bioorg. Med. Chem. Lett. 15 (2005) 3048
14. Edmondson S.D., Mastracchio A., Mathvink R.J., He J., Harper B., Park Y.-J., Beconi M., Di Salvo J., Eiermann G.J., He H., Leiting B., Leone J.F., Levorse D.A., Lyons K., Patel R.A., Patel S.B., Petrov A., Scapin G., Shang J., Sinha Roy R., Smith A., Wu J.K., Xu S., Zhu B., Thornberry N.A., and Weber A.E. J. Med. Chem. 49 (2006) 3614
15. Parmee E.R., He J., Mastracchio A., Edmondson S.D., Colwell L., Eiermann G., Feeney W.P., Habulihaz B., He H., Kilburn R., Leiting B., Lyons K., Marsilio F., Patel R.A., Petrov A., Di Salvo J., Wu J.K., Thornberry N.A., and Weber A.E. Bioorg. Med. Chem. Lett. 14 (2004) 43
16. Caldwell C.G., Chen P., He J., Parmee E.R., Leiting B., Marsilio F., Patel R.A., Wu J.K., Eiermann G.J., Petrov A., He H., Lyons K.A., Thornberry N.A., and Weber A.E. Bioorg. Med. Chem. Lett. 14 (2004) 1265
17. Klapars A., Huang X., and Buchwald S.L. J. Am. Chem. Soc. 124 (2002) 7421
18. For a related microwave-assisted sulfonamide arylation using catalytic CuI, see. He H., and Wu Y.-J. Tetrahedron Lett. 44 (2003) 3385
19. For assay conditions for the DPP-4 and QPP inhibition, see. Leiting B., Pryor K.D., Wu J.K., Marsilio F., Patel R.A., Craik C.S., Ellman J.A., Cummings R.T., and Thornberry N.A. Biochem. J. 371 (2003) 525
20. For assay conditions for DPP8 and DPP9, see Ref. 6.
21. Vinogradov S.A., and Wilson D.F. Tetrahedron Lett. 39 (1998) 8935
22. The X-ray crystal structure of 25 bound to the active site of DPP-4 (Fig. 2) established unambiguously the 1,4-trans relationship of the cyclohexyl substituents in this derivative. The single diastereomers 16-26 are all presumed to be trans by analogy.
23. The structure of DPP-4 in a complex with 25 has been deposited (PDB code 2OPH, RCSB ID code rcsb041425).
24. An alternative binding mode for compounds with similar structural homology was recently discovered in these laboratories. See. Xu J., Wei L., Mathvink R.J., Edmondson S.D., Eiermann G.J., He H., Leone J.F., Leiting B., Lyons K.A., Marsilio F., Patel R.A., Patel S.B., Petrov A., Scapin G., Wu J.K., Thornberry N.A., and Weber A.E. Bioorg. Med. Chem. Lett. 16 (2006) 5373
25. Qiao L., Baumann C.A., Crysler C.S., Ninan N.S., Abad M.C., Spurlino J.C., DesJarlais R.L., Kervinen J., Neeper M.P., Bayoumy S.S., Williams R., Deckman I.C., Dasgupta M., Reed R.L., Huebert N.D., Tomczuk B.E., and Moriarty K.J. Bioorg. Med. Chem. Lett. 16 (2006) 123