Identified a morpholinyl-4-piperidinylacetic acid derivative as a potent oral active VLA-4 antagonist

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 1, 2005, Pages 41-45

  Chiba, Jun ^a   MacHinaga, Nobuo ^a   Takashi, Tohru ^a   Ejima, Akio ^a   Takayama, Gensuke ^a   Yokoyama, Mika ^a   Nakayama, Atsushi ^a   Baldwin, John J ^b   McDonald, Edward ^b   Saionz, Kurt W ^b   Swanson, Robert ^b   Hussain, Zahid ^b   Wong, Angela ^b  

^a DAIICHI SANKYO CO   (Japan)

^b PHARMACOPEIA INC   (United States)

Author keywords

Asthma; Integrin; VLA 4

Indexed keywords

1 PIPERAZINYLACETIC ACID; 4 AMINOBENZOIC ACID; 4 PIPERIDINYLACETIC ACID; ACETIC ACID DERIVATIVE; ASCARIS ANTIGEN; MORPHOLINYL 4 PIPERIDINYLACETIC ACID; PROLYL 5 AMINOPENTANOIC ACID; UNCLASSIFIED DRUG; VALERIC ACID DERIVATIVE; VERY LATE ACTIVATION ANTIGEN 4;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG PENETRATION; DRUG POTENCY; DRUG STRUCTURE; IC 50; MALE; MEMBRANE PERMEABILITY; MOUSE; NONHUMAN; PLASMA CLEARANCE; RAT; RESPIRATORY TRACT INFLAMMATION; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ASTHMA; INTEGRIN ALPHA4BETA1; MICE; MORPHOLINES; PIPERIDINES;

ASCARIS; MURINAE;

EID: 9644291524     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.10.041     Document Type: Article

References (27)

1. R.O. Hynes Cell 48 1987 549
2. M.J. Elices, L. Osborn, Y. Takeda, C. Crouse, S. Luhowskyj, M.E. Hemler, and R.R. Lobb Cell 60 1990 577
3. J.L. Guan, and R.O. Hyens Cell 60 1990 53
4. E.A. Wayner, A. Garcia-Pardo, M.J. Humphries, J.A. McDonald, and W.G. Carter J. Cell. Biol. 109 1989 1321
5. S.A. Cunningham, J.M. Rodriguez, M.P. Arrate, T.M. Tran, and T.A. Brock J. Biol. Chem. 277 2002 27589
6. P. Vanderslice, R.J. Bidiger, D.G. Woodside, K.L. Berens, G.W. Holland, and R.A. Dixon Pulmonary Pharmacol. Therapeut. 17 2004 1
7. G.I. Yang, and W.H. Hagmann Med. Res. Rev. 23 2003 369
8. J.W. Tilley Expert Opin. Ther. Patents 12 2002 991
9. D.Y. Jackson Curr. Pharmaceut. Design 8 2002 1229
10. H. Yusuf-Makagiansar, M.E. Anderson, T.V. Yakovleva, J.S. Murray, and T.J. Siahaan Med. Res. Rev. 22 2002 146
11. Holland, G. W.; Biediger, R. J.; Vanderslice, P.; Annual Report in Medicinal Chemistry Doherty, A. M., Ed.; Academic: New York, 2002; Vol. 37, p 65
12. J.R. Porter IDrugs 3 2000 788
13. K. Lin, H.S. Ateenq, S.H. Hsiunig, L.T. Chong, C.N. Zimmerman, A. Castro, W.C. Lee, C.E. Hammond, S. Kalkunte, L.L. Chen, R.B. Pepinsky, D.R. Leone, A.G. Sprague, W.M. Abraham, A. Gill, R.R. Lobb, and S.P. Adams J. Med. Chem. 42 1999 920
14. T.A. Yednock, C. Cannon, L.C. Fritz, F. Sanchez-Madrid, L. Steinman, and N. Karin Nature 356 1992 63
15. P.S. Piraino, T.A. Yednock, S.B. Freedman, E.K. Messersmith, M.A. Pleiss, C. Vandevert, E.D. Thorsett, and S.J. Karlik J. Neuroimmunol. 131 2002 147
16. D. Seiffge J. Rheumatol. 23 1996 2086
17. D.K. Podolsky N. Engl. J. Med. 325 1991 928
18. F. Powrie, and M.W. Leach Ther. Immunol. 2 1995 115
19. D.H. Miller, O.A. Khan, W.A. Sheremata, L.D. Blumhardt, G.P. Rice, M.A. Libonati, A.J. Willmer-Hulme, C.M. Dalton, K.A. Miszkiel, and P.W. O'Connor N. Engl. J. Med. 348 2003 15
20. S. Ghosh, E. Goldin, F.H. Gordon, H.A. Malchow, J.R. Madsen, P. Rutgeerts, P. Vynálek, Z. Zádorová, T. Palmer, and S. Donoghue N. Engl. J. Med. 348 2003 24
21. G.T. Bolger Curr. Opin. Anti-inflammat. Immunodulat. Investigat. Drugs 2 2002 108
22. See Ref. 5a
23. (S)-Morpholinic acid derivative (6; P = Z, see Scheme 1) was synthesized as reported by: Y. Kogami, and K. Okawa Bull. Chem. Soc. Jpn. 60 1987 2963
24. 2). Then 50 μL of compound solution was distributed to the wells, followed by 50 μL of 2 nM of Eu-labeled Human VCAM-1/Fc Chimera diluted with the Wash Buffer (final concentration: 1 nM). The plates were incubated for 60 min at room temperature, and the wells were washed four times with 300 μL of chilled Wash Buffer. Finally 100 μL of the enhancement solution (Perkin-Elmer Inc., Wellesley, USA) was added to each well. The plates were placed on a shaker for 5 min. Eu fluorescence was then measured in a time-resolved fluorometer (DELFIA Research fluorometer, model: 1234-001, Perkin-Elmer Inc., Wellesley, USA). The concentration of compound required for 50% inhibition in the assay was determined
25. Female mice received cyclophosphamide dissolved in water administered orally at a dose of 150 mg/10 mL/kg (day 0). An extract of 500 μg of Ascaris suum protein as antigen in 0.2 mL saline containing 4.5 mg aluminum hydroxide as adjuvant were prepared. On day 2, 0.2 mL of the antigen solution was injected intraperitoneally. On day 14, a booster dose of the same antigen solution was injected intraperitoneally. Finally on day 22, mice were anesthetized by intraperitoneal injection with 65 mg/10 mL/kg of pentobarbital sodium solution. After 10 min, mice were challenged intratracheally with 300 μg protein of the Ascaris suum extract. The test compound was given to the mice at 15 min before and 8, 24, and 32 h after the antigen challenge. Forty-eight hours later, the lungs of mice were lavaged via a tracheal polyethylene cannula (outside diameter 1.33 mm, Hibiki No. 4, Hibiki Co., Tokyo, Japan) with 2 × 0.5 mL Hank's balanced buffered salt solution supplemented with 0.05 mM potassium EDTA. The bronchial alveolar lavage (BAL) was performed, and the total numbers of cells in BAL fluid were counted, separately. Eosinophils numbers were expressed as the mean from each treatment group
26. P. Artursson J. Pharm. Sci. 79 1990 476
27. P. Artursson, and J. Karlsson Biochem. Biophys. Res. Commun. 175 1991 880