Novel class of benzoic acid ester derivatives as potent PDE4 inhibitors for inhaled administration in the treatment of respiratory diseases

Journal of Medicinal Chemistry

Volumn 57, Issue 3, 2014, Pages 793-816

  Armani, Elisabetta ^a   Amari, Gabriele ^a   Rizzi, Andrea ^a   Fanti, Renato De ^a   Ghidini, Eleonora ^a   Capaldi, Carmelida ^a   Carzaniga, Laura ^a   Caruso, Paola ^a   Guala, Matilde ^b,c   Peretto, Ilaria ^b,d   La Porta, Elena ^b,e   Bolzoni, Pier T ^a   Facchinetti, Fabrizio ^a   Carnini, Chiara ^a   Moretto, Nadia ^a   Patacchini, Riccardo ^a   Bassani, Franco ^a   Cenacchi, Valentina ^a   Volta, Roberta ^a   Amadei, Francesco ^a   Capacchi, Silvia ^a   Delcanale, Maurizio ^a   Puccini, Paola ^a   Catinella, Silvia ^a   Civelli, Maurizio ^a   Villetti, Gino ^a   more..

^a CHIESI FARMACEUTICI S P A   (Italy)

^b NiKem Research   (Italy)

^c Aptuit Inc   (United States)

^d Sicor Srl   (Italy)

^e Sintetica SA   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

ADMINISTRATION, INHALATION; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ASTHMA; BENZOATES; CELL LINE; CHRONIC DISEASE; CRYSTALLOGRAPHY, X-RAY; EOSINOPHILIA; ESTERS; GUINEA PIGS; HUMANS; LEUKOCYTES, MONONUCLEAR; LUNG; LUNG DISEASES, OBSTRUCTIVE; MOLECULAR DOCKING SIMULATION; OVALBUMIN; PHOSPHODIESTERASE 4 INHIBITORS; PROTEIN CONFORMATION; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84894049174     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401549m     Document Type: Article

References (43)

1. Page, C. P.; Spina, D. Phosphodiesterase inhibitors in the treatment of inflammatory diseases Handb. Exp. Pharmacol. 2011, 204, 391-414
2. Sanz, M. J.; Cortijo, J.; Morcillo, E. J. PDE4 inhibitors as new anti-inflammatory drugs: Effects on cell trafficking and cell adhesion molecule expression Pharmacol. Ther. 2005, 106, 269-297
3. Houslay, M. D.; Schafer, P.; Zhang, K. Y. Keynote review: Phosphodiesterase-4 as a therapeutic target Drug. Discovery Today 2005, 10, 1503-1510
4. Hatzelmann, A.; Morcillo, E. J.; Lungarella, G.; Adnot, S.; Sanjar, S.; Beume, R.; Schudt, C.; Tenor, H. The preclinical pharmacology of roflumilast-a selective oral phosphodiesterase4 inhibitor in development for chronic obstructive pulmonary disease Pulm. Pharmacol. Ther. 2010, 23, 235-256
5. Horowski, R.; Sastre-y-Hernandez, M. Clinical effects of neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients: Global evaluation of the preliminary reports Curr. Ther. Res. 1985, 38, 23-29
6. Beghè, B.; Rabe, F.; Fabbri, L. M. Phosphodiesterase-4 inhibitor therapy for lung diseases Am. J. Respir. Crit. Care Med. 2013, 188, 271-278
7. Compton, C. H.; Gubb, J.; Niemann, R.; Edelson, J.; Amit, O.; Bakst, A.; Ayres, J. C.; Creemers, J. P.; Schultze-Werninghaus, G.; Brambilla, C.; Barnes, N. C. Cylomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomized, dose-ranging study Lancet 2001, 358, 265-270
8. Calverley, P. M.; Sanchez-Toril, F.; McIvor, A.; Teichmann, P.; Bredenbroeker, D.; Fabbri, L. M. Effect of 1-year treatment with Roflumilast in severe chronic obstructive pulmonary disease Am. J. Respir. Crit. Care Med. 2007, 176, 154-161
9. Rennard, S. I.; Schachter, N.; Strek, M.; Rickard, K.; Amit, O. Cilomilast for COPD: Results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4 Chest 2006, 129, 56-66
10. Page, C. P.; Spina, D. Selective PDE inhibitors as novel treatments for respiratory disorders Curr. Opin. Pharmacol. 2012, 12, 275-286
11. Kranz, M.; Wall, M.; Evans, B.; Miah, A.; Ballantine, S.; Delves, C.; Dombroski, B.; Groos, J.; Schneck, J.; Villa, J. P.; Neu, M.; Somers, D. O. Identification of PDE4B over 4D subtype-selective inhibitors revealing an unprecedented binding mode Bioorg. Med. Chem. 2009, 17, 5336-5341
12. Robichaud, A.; Stamatiou, P. B.; Jin, S. L. C.; Lachance, N.; MacDonald, D.; Laliberte, F.; Liu, S.; Huang, Z.; Conti, M.; Chan, C. C. Deletion of phosphodiesterase 4D in mice shortens alpha2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis J. Clin. Invest. 2002, 110, 1045-1052
13. Souness, J. E.; Rao, S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterase Cell. Signalling 1997, 9, 227-236
14. Burgin, A. B.; Magnusson, O. T.; Singh, J.; Witte, P.; Staker, B. R.; Bjornsson, J. M.; Thorsteinsdottir, M.; Hrafnsdottir, S.; Hagen, T.; Kiselyov, A. S.; Stewart, L. J.; Gurney, M. E. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety Nat. Biotechnol. 2010, 28, 63-70
15. Gross, P. M.; Wall, K. M.; Pang, J J.; Shaver, S. W.; Wainman, D.S. Microvascular specialization promoting rapid interstial solute dispersion in nucleus tractus solitaries Am. J. Physiol. 1990, 259, R1131-R1138
16. Okuda, S.; Honda, M.; Ito, Y.; Aihara, E.; Kato, S.; Mitsufuji, S.; Yoshikawa, T.; Takeuchi, K. Phosphodiesterase isozymes involved in regulating acid secretion in the isolated mouse stomach J. Physiol. Pharmacol. 2009, 60, 183-190
17. Kuss, H.; Hoefgen, N.; Johanssen, S.; Kronbach, T.; Rundfeldt, C. In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4- fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration J. Pharmacol. Exp. Ther. 2003, 307, 373-385
18. Duplantier, A. J.; Bachert, E. L.; Cheng, J. B.; Cohan, V. L.; Jenkinson, T. H.; Kraus, K. G.; McKechney, M. W.; Pillar, J. D.; Watson, J. W. SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase J. Med. Chem. 2007, 50, 344-349
19. Phillips, P.; Bennetts, M.; Banner, K.; Ward, J.; Wessels, D.; Fuhr, R. The PDE4 inhibitor UK-500 001 does not significantly inhibit airway responses to allergen and histamine Eur. Respir. J. 2007, 491s
20. Vestbo, J.; Tan, L.; Atkinsons, G.; Ward, J. The UK-500,001 Global Study Team. A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD Eur. Respir. J. 2009, 33, 1039-1044
21. Tralau-Stewart, C. J.; Williamson, R. A.; Nials, A. T.; Gascoigne, M.; Dawson, J.; Hart, G. J.; Angell, A. D. R.; Solanke, Y. E.; Lucas, F. S.; Wiseman, J.; Ward, P.; Ranshaw, L. E.; Knowles, R. G. GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: In vitro, kinetic, and in vivo characterization J. Pharmacol. Exp. Ther. 2011, 337, 145-154
22. Pages, L.; Gavaldà, A.; Lehner, M. D. PDE4 inhibitors: A review of current developments (2005-2009) Expert Opin. Ther. Pat. 2009, 19, 1501-1519
23. Singh, D.; Petavy, F.; Macdonald, A. J.; Lazaar, A. L.; O'Connor, B. J. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma Respir. Res. 2010, 1, 26-34
24. Lazaar, A. L.; Mistry, S.; Barrett, C.; Lulic-Burns, Z. The IPC 101939 Study Team. A 4-week randomized study of the safety and tolerability of the inhaled PDE4 inhibitor GSK256066 in COPD patients Am. J. Respir. Crit. Care Med. 2010, 181, A4444
25. Card, G. L.; England, B. P.; Suzuki, Y.; Fong, D.; Powell, B.; Lee, B.; Luu, C.; Tabrizizad, M.; Gillette, S.; Ibrahim, P. N.; Artis, D. R.; Bollag, G.; Milburn, M. V.; Kim, S. H.; Schlessinger, J.; Zhang, K. Y. J. Structural basis for the activity of drugs that inhibit phosphodiesterases Structure 2004, 12, 2233-2247
26. Gleeson, M. P. Plasma Protein Binding Affinity and Its Relationship to Molecular Structure: An In-silico Analysis J. Med. Chem. 2007, 50, 101-112
27. ACD/LogD release 12.00; Advanced Chemistry Development, Inc.: Toronto, Canada.
28. Medley, H.; Orozoco, S.; Allen, A. Efficacy and safety profile of fluticasone furoate administered once daily in the morning or evening: A randomized, double-blind, double-dummy, placebo-controlled trial in adult and adolescent patients with persistent bronchial asthma Clin. Ther. 2012, 34, 1683-1695
29. Delcanale, M.; Amari, G.; Armani, E. Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors. PCT Int. Appl. WO2008006509, February 12, 2009.
30. Amari, G.; Aquino, G.; Armani, E. Synthesis, in vitro and in vivo characterization of novel enolesters as PDE4 inhibitors. Frontiers in Medicinal Chemistry Meeting, Stockholm, Sweden, June 19-21, 2011.
31. Bethke, T. D.; Boehmer, G. M.; Hermann, R.; Hauns, B.; Fux, R.; Moerike, K.; David, M.; Knoerzer, D.; Wurst, W.; Gleiter, C. H. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor J. Clin. Pharmacol. 2007, 47, 26-36
32. Hatzelmann, A.; Schudt, C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro J. Pharmacol. Exp. Ther. 2001, 297, 267-279
33. Franova, S.; Joskova, M.; Sadlonova, V.; Pavelcikova, D.; Mesarosova, L.; Novakova, E.; Sutovska, M. Experimental model of allergic asthma Adv. Exp. Med. Biol. 2013, 756, 49-55
34. Torphy, T. J; Zhou, H. L.; Cieslinski, L. B. Stimulation of beta adrenoceptors in a human monocyte cell line (U937) up-regulates cyclic AMP-specific phosphodiesterase activity J. Pharmacol. Exp. Ther. 1992, 263, 1195-1205
35. Cooper, N.; Teixeira, M. M.; Warneck, J.; Miotla, J. M.; Wills, R. E.; Macari, D. M.; Gristwood, R. W.; Hellewell, P. G. A comparison of the inhibitory activity of PDE4 inhibitors on leukocyte PDE4 activity in vitro and eosinophil trafficking in vivo Br. J. Pharmacol. 1999, 126, 1863-1871
36. Gietzen, K.; Sadorf, I.; Bader, H. A model for the regulation of the calmodulin-dependent enzymes erythrocyte Ca2+-transport ATPase and brain phosphodiesterase by activators and inhibitors Biochem. J. 1982, 207, 541-548
37. Schudt, C.; Winder, S.; Muller, B.; Ukena, D. Zardaverine as a selective inhibitor of phosphodiesterase isozymes Biochem. Pharmacol. 1991, 42, 153-162
38. Baehr, W.; Devlin, M. J.; Applebury, M. L. Isolation and characterization of cGMP phosphodiesterase from bovine rod outer segments J. Biol. Chem. 1979, 254, 11669-11677
39. Thompson, W. J.; Appleman, M. M. Multiple cyclic nucleotide phosphodiesterase activities from rat brain Biochemistry 1971, 10, 311-316
40. Leo, A.; Hansch, C.; Elkins, D. Partition coefficients and their uses Chem. Rev. 1971, 71, 525-616
41. Sangster, J. Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry; Wiley: New York, 1997.
42. Maestro, version 9.2; Schrödinger, LLC: New York, 2011.
43. Glide, version 5.7; Schrödinger, LLC: New York, 2011.