Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension

Journal of Medicinal Chemistry

Volumn 59, Issue 17, 2016, Pages 7901-7914

  Shaw, Duncan E ^a   Baig, Ferheen ^b   Bruce, Ian ^c   Chamoin, Sylvie ^e   Collingwood, Stephen P ^c   Cross, Sarah ^a   Dayal, Satish ^b   Drückes, Peter ^e   Furet, Pascal ^e   Furminger, Vikki ^c   Haggart, Deborah ^f   Hussey, Martin ^d   Konstantinova, Irena ^d   Loren, Jon C ^f   Molteni, Valentina ^f   Roberts, Sonia ^d   Reilly, John ^c   Saunders, Alex M ^c   Stringer, Rowan ^b   Sviridenko, Lilya ^c   Thomas, Matthew ^d   Thomson, Christopher G ^a   Tomlins, Christine ^d   Wen, Ben ^f   Yeh, Vince ^f   Pearce, Andrew C ^d   more..

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^b Metabolism and Pharmacokinetics   (United Kingdom)

^c NIBR Horsham   (United Kingdom)

^d Respiratory Disease TA   (United Kingdom)

^e Global Discover Chemistry   (Switzerland)

^f GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 [ 1 METHYL 1H PYRAZOL 5 YL] N [ 2 METHYL 5 ( 2 ( 4 METHYLPIPERAZIN 1 YL)BENZYLCARBAMOYL) 3 YL]PYRAZOLO[ 1,5 A]PYRIDINE 3 CARBOXAMIDE; ANGIOGENESIS INHIBITOR; ANTIHYPERTENSIVE AGENT; IMATINIB; MONOCROTALINE; N [ 2 FLUORO 5 [ 2 ( 4 METHYLPIPERAZIN 1 YL)BENZYLCARBAMOYL]PHENYL] 6 ( 1 METHYL 1H PYRAZOL 5 YL)PYRAZOLO[ 1,5 A]PYRIDINE 3 CARBOXAMIDE; N [ 2 FLUORO 5 [( 2 ( 4 METHYLPIPERAZIN 1 YL)BENZYL)CARBAMOYL]PHENYL] 7 ( 1 METHYL 1H PYRAZOL 5 YL)IMIDAZO[ 1,2 A]PYRIDINE 3 CARBOXAMIDE; N [ 5 [ 2 ( 2,2 DIMETHYLPYRROLIDIN 1 YL)ETHYLCARBAMOYL] 2 METHYLPYRIDIN 3 YL] 6 ( 1 METHYL 1H PYRAZOL 4 YL)PYRAZOLO[ 1,5 A]PYRIDINE 3 CARBOXAMIDE; N [ 5 [( 2 ( 2,2 DIMETHYLPYRROLIDIN 1 YL)ETHYL)CARBAMOYL] 2 FLUOROPHENYL] 7 ( 1 METHYL 1H PYRAZOL 4 YL)IMIDAZO[ 1,2 A]PYRIDINE 3 CARBOXAMIDE; N [ 5 [( 2 ( 2,6 DIMETHYLPIPERIDIN 1 YL)ETHYL)CARBAMOYL] 2 FLUOROPHENYL] 7 ( 1 METHYL 1H PYRAZOL 5 YL)IMIDAZO[ 1,2 A]PYRIDINE 3 CARBOXAMIDE; N [ 5 [( 3,4 DIFLUOROBENZYL)CARBAMOYL] 2 FLUOROPHENYL] 7 ( 1 METHYL 1H PYRAZOL 5 YL)IMIDAZO[ 1,2 A]PYRIDINE 3 CARBOXAMIDE; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PLATELET DERIVED GROWTH FACTOR RECEPTOR INHIBITOR; UNCLASSIFIED DRUG; ARTIFICIAL MEMBRANE; N-(5-(2-(2,2-DIMETHYLPYRROLIDIN-1-YL)ETHYLCARBAMOYL)-2-METHYLPYRIDIN-3-YL)-6-(1-METHYL-1H-PYRAZOL-4-YL)PYRAZOLO(1,5-A)PYRIDINE-3-CARBOXAMIDE; NICOTINAMIDE; PLATELET DERIVED GROWTH FACTOR ALPHA RECEPTOR; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; PYRAZOLE DERIVATIVE; STEM CELL FACTOR RECEPTOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BILIARY CLEARANCE; CACO 2 CELL LINE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EFFICACY; DRUG MECHANISM; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG SOLUBILITY; IC50; IN VITRO STUDY; IN VIVO STUDY; LIPOPHILICITY; LUNG DISEASE; LUNG PARENCHYMA; MONOCROTALINE-INDUCED PULMONARY HYPERTENSION; NONHUMAN; PHARMACODYNAMICS; PHARMACOKINETIC PARAMETERS; RAT; RECEPTOR OCCUPANCY; VOLUME OF DISTRIBUTION; AIRWAY REMODELING; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; ARTIFICIAL MEMBRANE; CELL LINE; CHEMISTRY; DRUG EFFECTS; HYPERTENSION, PULMONARY; INHALATIONAL DRUG ADMINISTRATION; LUNG; MOLECULAR DOCKING; PATHOLOGY; PERMEABILITY; STRUCTURE ACTIVITY RELATION; SYNTHESIS; VASCULAR REMODELING; VASCULAR SMOOTH MUSCLE; VASCULARIZATION;

ADMINISTRATION, INHALATION; AIRWAY REMODELING; ANIMALS; CELL LINE; CELL PROLIFERATION; HYPERTENSION, PULMONARY; LUNG; MEMBRANES, ARTIFICIAL; MOLECULAR DOCKING SIMULATION; MUSCLE, SMOOTH, VASCULAR; NIACINAMIDE; PERMEABILITY; PROTO-ONCOGENE PROTEINS C-KIT; PYRAZOLES; RATS; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR ALPHA; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR BETA; RECEPTORS, PLATELET-DERIVED GROWTH FACTOR; STRUCTURE-ACTIVITY RELATIONSHIP; VASCULAR REMODELING;

EID: 84986313861     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00703     Document Type: Article

References (22)

1. Ghofrani, H. A.; Wilkins, M. W.; Rich, S. Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension Circulation 2008, 118, 1195-1201 10.1161/CIRCULATIONAHA.106.674002
2. Badesch, D. B.; Champion, H. C.; Gomez Sanchez, M. A.; Hoeper, M. M.; Loyd, J. E.; Manes, A.; McGoon, M.; Naeige, R.; Olschewski, H.; Oudiz, R. J.; Torbicki, A. Diagnosis and assessment of pulmonary arterial hypertension J. Am. Coll. Cardiol. 2009, 54, S55-S66 10.1016/j.jacc.2009.04.011
3. Corris, P.; Degano, B. Severe pulmonary arterial hypertension: treatment options and the bridge to transplantation Eur. Respir. Rev. 2014, 23, 488-497 10.1183/09059180.00007214
4. Perros, F.; Montani, D.; Dorfmuller, P.; Durand-Gasselin, I.; Tcherakian, C.; Le Pavec, J.; Mazmanian, M.; Fadel, E.; Mussot, S.; Mercier, O.; Hervé, P.; Emilie, D.; Eddahibi, S.; Simonneau, G.; Souza, R.; Humbert, M. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension Am. J. Respir. Crit. Care Med. 2008, 178, 81-88 10.1164/rccm.200707-1037OC
5. Ghofrani, A.; Morrell, N. W.; Hoeper, M. M.; Olschewski, H.; Peacock, A. J.; Barst, R. J.; Shapiro, S.; Golpon, H.; Toshner, M.; Grimminger, F.; Pascoe, S. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy Am. J. Respir. Crit. Care Med. 2010, 182, 1171-1177 10.1164/rccm.201001-0123OC
6. Frost, A. E.; Barst, R. J.; Hoeper, M. M.; Chang, H.-J.; Frantz, R. P.; Fukumoto, Y.; Nazzareno, G. N.; Hassoun, P. M.; Klose, H.; Matsubara, H.; Morrell, N. W.; Peacock, A. J.; Pfeifer, M.; Simonneau, G.; Tapson, V. F.; Torres, F.; DarioVizza, C.; Lawrence, D.; Yang, W.; Felser, J. M.; Quinn, D. and Ghofrani, Long-term safety and efficacy of imatinib in pulmonary arterial hypertension J. Heart. Lung. Transplant. 2015, 34, 1366-1375 10.1016/j.healun.2015.05.025
7. Cooper, E. A.; Ferguson, D.; Grime, K. Optimisation of DMPK by the inhaled route: challenges and approaches Curr. Drug Metab. 2012, 13, 457-473 10.2174/138920012800166571
8. Tronde, A.; Norden, B.; Marchner, H.; Wendel, A.; Lennernäs, H.; Bengtsson, U. Pulmonary absorption rate and bioavailability of drugs in vivo in rats: structure-absorption relationships and physicochemical profiling of inhaled drugs J. Pharm. Sci. 2003, 92, 1216-1233 10.1002/jps.10386
9. Cazzola, M.; Page, C. P.; Calzetta, L.; Matera, M. G. Pharmacology and therapeutics of bronchodilators Pharmacol. Rev. 2012, 64, 450-504 10.1124/pr.111.004580
10. Mol, C. D.; Dougan, D. R.; Schneider, T. R.; Skene, R. J.; Kraus, M. L.; Scheibe, D. N.; Snell, G. P.; Zou, H.; Sang, B. C.; Wilson, K. P. Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase J. Biol. Chem. 2004, 279, 31655-31663 10.1074/jbc.M403319200
11. Bruce, I.; Chamoin, S.; Collingwood, S. P.; Furet, P.; Furminger, V.; Lewis, S.; Loren, J. C.; Molteni, V.; Saunders, A. M.; Shaw, D.; Sviridenko, L.; Thomson, C.; Yeh, V.; Janus, D.; West, R. Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension. Patent WO2013030802, March 7, 2013.
12. DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A. Privileged structures: applications in drug discovery Comb. Chem. High Throughput Screening 2004, 7, 473-494 10.2174/1386207043328544
13. Valko, K.; Du, C. M.; Bevan, C. D.; Reynolds, D. P.; Abraham, M. H. Rapid-gradient HPLC method for measuring drug interactions with immobilized artificial membrane: comparison with other lipophilicity measures J. Pharm. Sci. 2000, 89, 1085-1096 10.1002/1520-6017(200008)89:8<1085::AID-JPS13>3.0.CO;2-N
14. Mallik, R.; Yoo, M. J.; Briscoe, C. J.; Hage, D. S. Analysis of drug-protein binding by ultra fast affinity chromatography using immobilized human serum albumin J. Chromatogr. A 2010, 1217, 2796-2803 10.1016/j.chroma.2010.02.026
15. Reilly, J.; Etheridge, D.; Everatt, B.; Jiang, Z.; Springer, C.; Fairhurst, R. A. Studies in drug albumin binding using HSA and RSA affinity methods J. Liq. Chromatogr. Relat. Technol. 2011, 34, 317-327 10.1080/10826076.2011.548299
16. Supplied by Cell Signaling Technology (www.cellsignal.com).
17. Hollósy, F.; Valkó, K.; Hersey, A.; Nunhuck, S.; Kéri, G.; Bevan, C. Estimation of volume of distribution in humans from high throughput HPLC-based measurements of human serum albumin binding and immobilized artificial membrane partitioning J. Med. Chem. 2006, 49, 6958-71 10.1021/jm050957i
18. Jones, J. E.; Mendes, L.; Rudd, M. A.; Russo, G.; Loscalzo, J.; Zhang, Y.-Y. Serial noninvasive assessment of progressive pulmonary hypertension in a rat model Am. J. Physiol. Heart Circ. Physiol. 2002, 283, H364-H371 10.1152/ajpheart.00979.2001
19. Gomez-Arroyo, J. G.; Farkas, L.; Alhussaini, A. A.; Farkas, D.; Kraskauskas, D.; Voelkel, N. F.; Bogaard, H. J. The monocrotaline model of pulmonary hypertension in perspective Am. J. Physiol. Lung Cell Mol. Physiol. 2012, 302, L363-L369 10.1152/ajplung.00212.2011
20. Stenmark, K. R.; Meyrick, B.; Galie, N.; Mooi, W. J.; McMurtry, I. F. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure Am. J. Physiol. Lung Cell Mol. Physiol. 2009, 297, L1013-L1032 10.1152/ajplung.00217.2009
21. Bruce, I.; Chamoin, S.; Furet, P.; Furminger, V.; Lewis, S.; Loren, J.; Lin, L. V.; Molteni, V.; Saunders, A. M.; Shaw, D. E.; Turner, R.; Yeh, V. (2014) Solid forms of bicyclic heterocyclic derivatives as pdgf receptor mediators. Patent WO2014132220, September 4, 2014.
22. Fabian, M. A.; Biggs, W. H.; Treiber, D. K.; Atteridge, C. E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A. G.; Lelias, J. M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D. J. A small molecule-kinase interaction map for clinical kinase inhibitors Nat. Biotechnol. 2005, 23, 329-336 10.1038/nbt1068