A concise synthesis of an indenopyrrolidine-based dual α vβ3/αvβ5 integrin antagonist

Heterocycles

Volumn 62, Issue , 2004, Pages 543-557

  Luci, Diane K ^a   Santulli, Rosemary J ^a   Gauthier, Diane A ^a   Tounge, Brett A ^a   Ghosh, Shyamali ^a   Proost, Jef C ^a   Kinney, William A ^a   De Corte, Bart ^a   Galemmo Jr , Robert A ^a   Lewis, Joan M ^a   Dorsch, Warren E ^b   Wagaman, Michael W ^b   Damiano, Bruce P ^a   Maryanoff, Bruce E ^a  

^a J W Johnson Pharmaceutical Res I   (United States)

^b C B Research and Development Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA5BETA3 INTEGRIN; ALPHA5BETA3 INTEGRIN ANTAGONIST; ALPHA5BETA5 INTEGRIN; ALPHA5BETA5 INTEGRIN ANTAGONIST; CYCLOPENTANE; INDENOPYRROLIDINE; INTEGRIN; LIGAND; PYRROLIDINE DERIVATIVE; RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG;

ARTICLE; CONFORMATION; CYCLOADDITION; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; ISOMER; RIGIDITY;

EID: 0346459970     PISSN: 03855414     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (21)

1. W. H. Miller, R. M. Keenan, R. N. Willette, and M. W. Lark, DDT, 2000, 5, 397.
2. W. H. Miller, W. E. Bondinell, R. D. Cousins, K. F. Erhard, D. R. Jakas, R. M. Keenan, T. W. Ku, K. A. Newlander, S. T. Ross, R. C. Haltiwanger, J. Badbeer, F. H. Drake, M. Gowen, S. J. Hoffman, S-M. Hwang, I. E. James, M. W. Lark, B. Lechowska, D. J. Rieman, G. B. Stroup, J. A. Vasko-Moser, D. L. Zembryki, L. M. Azzarano, P. C. Adams, K. L. Salyers, B. R. Smith, K. W. Ward, K. O. Johanson, and W. F. Huffman, Bioorg. Med. Chem. Lett., 1999, 9, 1807.
3. The synthesis of 1 is contained in M. J. Costanzo, W. J. Hoekstra, and B. E. Maryanoff, WO2001/23376, 2001, Apr 5, and will also be published separately in manuscript form.
4. P. J. Coleman, B. C. Askew, J. H. Hutchinson, D. B. Whitman, J. J. Perkins, G. D. Hartman, G. A. Rodan, C-T. Leu, T. Prueksaritanont, C. Fernandez-Metzler, K. M. Merkle, J. J. Lynch, S. B. Rodan, and M. E. Duggan, Biorg. Med. Chem. Lett., 2002, 12, 2463.
5. V. Paragamian, U. S. Patent 3,462,443, 1969, Aug 19; C. E. Cook, M. C. Wani, J. M. Jump, Y-W. Lee, P. A. Fail, S. A. Anderson, Y-Q. Gu, and V. Petrow, J. Med. Chem., 1995, 38, 753.
6. V. Paragamian, U. S. Patent 3,462,443, 1969, Aug 19; C. E. Cook, M. C. Wani, J. M. Jump, Y-W. Lee, P. A. Fail, S. A. Anderson, Y-Q. Gu, and V. Petrow, J. Med. Chem., 1995, 38, 753.
7. B. C. Askew, P. J. Coleman, M. E. Duggan, W. Halczenko, G. D. Hartman, C. A. Hunt, J. H. Hutchinson, R. S. Meissner, M. A. Patane, G. R. Smith, and J. Wang, U. S. Patent 6,048,861, 2000, Apr. 11; N. S. Chandrakumar, B. N. Desai, B. Devadas, R. Huff, I. K. Khanna, S. N. Rao, J. G. Rico, T. E. Rogers, P. G. Ruminski, M. A. Russell, Y. Yu, A. F. Gasiecki, J. W. Malecha, and J. M. Miyashiro, WO99/52896, 1999, Oct. 21; M. E. Duggan, G. D. Hartman, R. S. Meissner, and J. J. Perkins, U. S. Patent 6,410,526, 2002, Jun. 25.
8. B. C. Askew, P. J. Coleman, M. E. Duggan, W. Halczenko, G. D. Hartman, C. A. Hunt, J. H. Hutchinson, R. S. Meissner, M. A. Patane, G. R. Smith, and J. Wang, U. S. Patent 6,048,861, 2000, Apr. 11; N. S. Chandrakumar, B. N. Desai, B. Devadas, R. Huff, I. K. Khanna, S. N. Rao, J. G. Rico, T. E. Rogers, P. G. Ruminski, M. A. Russell, Y. Yu, A. F. Gasiecki, J. W. Malecha, and J. M. Miyashiro, WO99/52896, 1999, Oct. 21; M. E. Duggan, G. D. Hartman, R. S. Meissner, and J. J. Perkins, U. S. Patent 6,410,526, 2002, Jun. 25.
9. B. C. Askew, P. J. Coleman, M. E. Duggan, W. Halczenko, G. D. Hartman, C. A. Hunt, J. H. Hutchinson, R. S. Meissner, M. A. Patane, G. R. Smith, and J. Wang, U. S. Patent 6,048,861, 2000, Apr. 11; N. S. Chandrakumar, B. N. Desai, B. Devadas, R. Huff, I. K. Khanna, S. N. Rao, J. G. Rico, T. E. Rogers, P. G. Ruminski, M. A. Russell, Y. Yu, A. F. Gasiecki, J. W. Malecha, and J. M. Miyashiro, WO99/52896, 1999, Oct. 21; M. E. Duggan, G. D. Hartman, R. S. Meissner, and J. J. Perkins, U. S. Patent 6,410,526, 2002, Jun. 25.
10. R. Achini, Helv. Chim. Acta, 1981, 64, 2203.
11. D. A. Nugiel, Tetrahedron Lett., 2001, 42, 3545 and references sited therein.
12. Can be prepared in one step from indanone: K. C. Nicolaou, T. Montagnon, and P. S. Baran, Angew. Chem., Int. Ed., 2002, 41, 1386.
13. 2, 150 mM NaCl) was immobilized (1 μg/mL) on Immulon 96 well plates (Dynex Technologies) overnight at 4°C. Plates were blocked with 3% BSA in Tris buffer for 2 h at 37°C. Plates were then rinsed 2X in assay buffer (Tris buffer with 0.3% BSA and 0.2% Tween-20). Five minutes prior to the addition of 4 nM vitronectin (Sigma Chemical Co.), compounds were added to wells in duplicate. Following 3 h at 37°C, plates were washed 5 times in assay buffer. An anti-human vitronectin IgG rabbit polyclonal antibody (Calbiochem Inc.) was added (1:2000) and plates were incubated for 1 h at room temperature. VectaStain ABC peroxidase kit reagents (Vector Laboratories) employing a biotin labeled anti-rabbit IgG, were utilized for detection of bound antibody (490 nm); J. Hoekstra, M. P. Beavers, P. Andrade-Gordon, M. F. Evangelisto, P. M. Keane, J. B. Press, K. A. Tomko, F. Fan, M. Kloczewiak, K. H. Mayo, K. A. Durkin, and D. C. Liotta, J. Med. Chem., 1995, 38, 1582.
14. 2, 150 mM NaCl) was immobilized (1 μg/mL) on Immulon 96 well plates (Dynex Technologies) overnight at 4°C. Plates were blocked with 3% BSA in Tris buffer for 2 h at 37°C. Plates were then rinsed 2X in assay buffer (Tris buffer with 0.3% BSA and 0.2% Tween-20). Five minutes prior to the addition of 4 nM vitronectin (Sigma Chemical Co.), compounds were added to wells in duplicate. Following 3 h at 37°C, plates were washed 5 times in assay buffer. An anti-human vitronectin IgG rabbit polyclonal antibody (Calbiochem Inc.) was added (1:2000) and plates were incubated for 1 h at room temperature. VectaStain ABC peroxidase kit reagents (Vector Laboratories) employing a biotin labeled anti-rabbit IgG, were utilized for detection of bound antibody (490 nm); J. Hoekstra, M. P. Beavers, P. Andrade-Gordon, M. F. Evangelisto, P. M. Keane, J. B. Press, K. A. Tomko, F. Fan, M. Kloczewiak, K. H. Mayo, K. A. Durkin, and D. C. Liotta, J. Med. Chem., 1995, 38, 1582.
15. The X-Ray structure was obtained from Crystalytics Company, Lincoln, Nebraska.
16. The right turn is defined as the clockwise rotation from the A-ring to C-ring with the carboxylic acid group directed away from the viewer.
17. Each ligand was docked into the X-Ray structure by aligning the basic and acidic motifs. In order to place the turn motif, energies were calculated for several conformations in which the turn was rotated about the long axis of the molecule. (Energy minimization runs: Polak-Ribier Conjugate (PRCG) method, in water, OPLS-AA, constant dielectric constant of 1, sidechain atoms in a 8.0 Å radius around the active site and the ligand were allowed to move, and all other atoms were held frozen) The minimum energy poses from these studies are shown in Figure 4. All the simulations were performed using MacroModel (Schrödinger, Inc., Portland, OR., 2003).
18. J-P. Xiong, T. Stehle, R. Zhang, A. Joachimiak, M. Frech, S. L. Goodman, and M. A. Arnaout, Science, 2002, 296, 151.
19. K. Urbahns, M. Härter, A. Vaupel, M. Albers, D. Schmidt, U. Brüggemeier, B. Stelte-Ludwig, C. Gerdes, and H. Tsujishita, Biorg. Med. Chem. Lett., 2003, 13, 1071.
20. These in vitro pharmacokinetic assays were preformed at Absorption Systems, Exton, PA.
21. C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, Adv. Drug Delivery Rev., 1997, 23, 3.