Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3 763
(3) Xu, K.; Bastia, E.; Schwarzschild, M. Therapeutic potential of
adenosine A2A receptor antagonists in Parkinson’s disease. Phar-
macol. Ther. 2005, 105, 267–310.
(4) Simola, N.; Morelli, M.; Pinna, A. Adenosine A2A receptor an-
tagonists and Parkinson’s disease: State of the art and future
directions. Curr. Pharm. Des. 2008, 14, 1475–1489.
(5) Baraldi, P. G.; Tabrizi, M. A.; Gessi, S.; Borea, A. P. Adenosine
receptor antagonists: Translating medicinal chemistry and phar-
macology into clinical utility. Chem. Rev. 2008, 108, 238–263.
(6) Moro, S.; Gao, Z.-G.; Jacobson, K. A.; Spalluto, G. Progress in the
pursuit of therapeutic adenosine receptor antagonists. Med. Res.
Rev. 2006, 26, 131–159.
(18) Gillespie, R. J.; Cliffe, I. A.; Dawson, C. E.; Dourish, C. T.; Gaur, S.;
Giles, P. R.; Jordan, A. M.; Knight, A. R.; Lawrence, A.; Lerpiniere,
J.; Misra, A.; Pratt, R. M.; Todd, R. S.; Upton, R.; Weiss, S. M.;
Williamson, D. S. Antagonists of the human adenosine A2A recep-
tor. Part 2: Design and synthesis of 4-arylthieno[3,2-d]pyrimidine
derivatives. Bioorg. Med. Chem. Lett. 2008, 18, 2920–2923.
(19) Gillespie, R. J.; Bamford, S. J.; Gaur, S.; Jordan, A. M.; Lerpiniere,
J.; Mansell, H. L.; Stratton, G. C. Antagonists of the human A2A
receptor. Part 5: Highly bio-available pyrimidine-4-carboxamides.
Bioorg. Med. Chem. Lett. 2009, 19, 2664–2667.
(20) Gillespie, R. J.; Bamford, S. J.; Clay, A.; Gaur, S.; Haymes, T.;
Jackson, P. S.; Jordan, A. M.; Klenke, B.; Leonardi, S.; Liu, J.;
Mansell, H. L.; Ng, S.; Saadi, M.; Simmonite, H.; Stratton, G. C.;
Todd, R. S.; Williamson, D. S.; Yule, I. A. Antagonists of the
human A2A receptor. Part 6: Further optimization of pyrimidine-4-
carboxamides. Bioorg. Med. Chem. 2009, 17, 6590–6605.
ꢀ
(7) Yuzlenko, O.; Kiec-Kononowicz, K. Potent adenosine A1 and A2A
receptor antagonists: Recent developments. Curr. Med. Chem.
2006, 13, 3609–3625.
(8) Sams, A. G.; Mikkelsen, G. K.; Larsen, M.; Torup, L.; Brennum,
L. T.; Schrøder, T. J.; Bang-Andersen, B. Hit-to-lead optimization
of a series of carboxamides of ethyl 2-amino-phenylthiazole-5-
carboxylates as novel adenosine A2A receptor antagonists. Bioorg.
Med. Chem. Lett. 2010, 20, 5241–5244.
(21) Cole, A. G.; Stauffer, T. M.; Rokosz, L. L.; Metzger, A.; Dillard,
L. W.; Zeng, W.; Henderson, I. Synthesis of 2-amino-5-benzoyl-
4-(2-furyl)thiazoles as adenosine A2A receptor antagonists. Bioorg.
Med. Chem. Lett. 2009, 19, 378–381.
(22) Jenner, P. Istradefylline, a novel adenosine A2A receptor antago-
nist, for the treatment of Parkinson’s disease. Expert Opin. Invest.
Drugs 2005, 14, 729–738.
(9) Zhang, X.; Tellew, J. E.; Luo, Z.; Moorjani, M.; Lin, E.; Lanier,
M. C.; Chen, Y.; Williams, J. P.; Saunders, J.; Lechner, S. M.;
Markison, S.; Joswig, T.; Petroski, R.; Piercey, J.; Kargo, W.;
Malany, S.; Santos, M.; Gross, R. S.; Wen, J.; Jalali, K.; O’Brien,
Z.; Stotz, C. E.; Crespo, M. I.; Dias, J.-L.; Slee, D. H. Lead
optimization of 4-acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyri-
dylpyrimidines as A2A adenosine receptor antagonists fro the treat-
ment of Parkinson’s disease. J. Med. Chem. 2008, 51, 7099–7110.
(10) Slee, D. H.; Chen, Y.; Zhang, X.; Moorjani, M.; Lanier, M. C.; Lin,
E.; Rueter, J. K.; Williams, J. P.; Lechner, S. M.; Markison, S.;
Malany, S.; Santos, M.; Gross, R. S.; Jalali, K.; Sai, Y.; Zuo, Z.;
Yang, C.; Castro-Palomino, J. C.; Crespo, M. I.; Pratt, R. M.;
Dias, J.-L.; Saunders, J. 2-Amino-N-pyrimidin-4-ylacetamides as
A2A receptor antagonists: 1. Structure-activity relationships and
optimization of heterocyclic substituents. J. Med. Chem. 2008, 51,
1719–1729.
(23) Neustadt, B. R.; Hao, J.; Lindo, N.; Greenlee, W. J.; Stamford,
A. W.;Tulshian, D.; Ongini, E.; Hunter, J.;Monopoli, A.;Bertorelli,
R.; Foster, C.; Arik, L.; Lachowicz, J.; Ng, K.; Feng, K.-I. Potent,
selective, and orally active adenosine A2A receptor antagonists:
Arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]-
pyrimidines. Bioorg. Med. Chem. Lett. 2006, 17, 1376–1380.
(24) Jaakola, V.-P.; Griffith, M. T.; Hanson, M. A.; Chezerov, V.;
Chien, E. Y. T.; Lane, J. R.; IJzerman, A. P.; Stevens, R. C. The 2.6
angstrom crystal structure of a human A2A adenosone recpetor
bound to an antagonist. Science 2008, 322, 1211–1217.
(25) Carlsson, J.; Yoo, L.; Gao, Z.-G.; Irwin, J. J.; Shoishet, B. K.;
Jacobson, K. A. Structure-based discovery of A2A adenosine
receptor ligands. J. Med. Chem. 2010, 53, 3748–3755.
(11) Slee, D. H.; Zhang, X.; Moorjani, M.; Klenk, D. C.; Lanier, M. C.;
Chen, Y.; Rueter, J. K.; Lechner, S. M.; Markison, S.; Malany, S.;
Joswig, T.; Santos, M.; Gross, R. S.; Williams, J. P.; Castro-
Palomino, J. C.; Crespo, M. I.; Pratt, R. M.; Gual, S.; Dias,
J.-L.; Wen, J.; O’Brien, Z.; Saunders, J. Identification of novel, water-
soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor
antagonists with in vivo efficacy. J. Med. Chem. 2008, 51, 400–406.
(12) Slee, D. H.; Moorjani, M.; Zhang, X.; Lin, E.; Lanier, M. C.; Chen,
Y.; Rueter, J. K.; Lechner, S. M.; Markison, S.; Malany, S.; Joswig,
T.; Santos, M.; Gross, R. S.; Williams, J. P.; Castro-Palomino,
J. C.; Crespo, M. I.; Pratt, R. M.; Gual, S.; Dias, J.-L.; Jalali, K.;
Sai, Y.; Zuo, Z.; Yang, C.; Wen, J.; O’Brien, Z.; Petroski, R.;
Saunders, J. 2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor
antagonists: 2. Reduction of hERG activity, observed species
selectivity, and structure-activity relationships. J. Med. Chem.
2008, 51, 1730–1739.
(26) Katritch, V.; Jaakola, V.-P.; Lane, J. R.; Lin, J.; IJzerman, A. P.;
Yeager, M.; Kufareva, I.; Stevens, R. C.; Abagyan, R. Structure-
based discovery of novel chemotypes for adenosine A2A receptor
antagonists. J. Med. Chem. 2010, 53, 1799–1809.
€
(27) Maestro v9.0, Schrodinger Inc.: Portland, OR, 2010.
(28) Higgs, C.; Beuming, T.; Sherman, W. Hydration site thermody-
namics explain SARs for thiazolylpurines analogues binding to the
A2A receptor. ACS Med. Chem. Lett. 2010, 1, 160–164.
(29) Lave, T.; Coassolo, P.; Reigner, B. Prediction of hepatic metabolic
clearance based on interspecies allometric scaling techniques and in
vitro-in vivo correlations. Clin. Pharmacokinet. 1999, 36, 211–231.
(30) Rowland, M.; Tozer, T. N. Clinical Pharmacokinetics: Concepts and
Applications; Lippincott, Williams & Wilkins: Philadelphia, PA, 1995.
(31) McGinnity, D. F.; Collington, J.; Austin, R. P.; Riley, R. J.
Evaluation of human pharmacokinetics, therapeutic dose and
exposure predictions using marketedoral drugs. Curr. Drug Metab.
2007, 8, 463–479.
(13) Shao, Y.; Cole, A. G.; Brescia, M.-R.; Qin, L.-Y.; Duo, J.; Stauffer,
T. M.; Rokosz, L. L.; McGuinness, B. F.; Henderson, I. Synthesis
and SAR studies of trisubstituted purinones as potent and selective
adenosine A2A receptor antagonists. Bioorg. Med. Chem. Lett.
2009, 19, 1399–1402.
(32) Mandhane, S. N.; Chopde, C. T.; Ghosh, A. K. Adenosine A2
receptors modulate haloperidol-induced catalepsy in rats. Eur. J.
Pharmacol. 1997, 328, 135–141.
€
(33) Muller, C. E. Prodrug approaches for enhancing the bioavailability
(14) Neustadt, B. R.; Liu, H.; Hao, J.; Greenlee, W. J.; Stamford, A. W.;
Foster, C.; Arik, L.; Lachowicz, J.; Zhang, H.; Bertorelli, R.;
Fredduzzi, S.; Varty, G.; Cohen-Williams, M.; Ng, K. Potent and
selective adenosine A2A receptor antagonists: 1,2,4-triazolo[1,5-c]-
pyrimidines. Bioorg. Med. Chem. Lett. 2009, 19, 967–971.
(15) Moorjani, M.; Luo, Z.; Lin, E.; Vong, B. G.; Chen, Y.; Zhang, X.;
Rueter, J. K.; Gross, R. S.; Lanier, M. C.; Tellew, J. E.; Williams,
J. P.; Lechner, S. M.; Malany, S.; Santos, M.; Crespo, M. I.; Dias,
J.-L.; Saunders, J.; Slee, D. H. 2,6-Diaryl-4-acylaminopyrimidines
as potent and selective adenosine A2A antagonists with improved
solubility and metabolic stability. Bioorg. Med. Chem. Lett. 2008,
18, 5402–5405.
of drugs with low solubility. Chem. Biodiversity 2009, 6, 2071–2083.
(34) Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.;
€
Jarvinen, T.; Savolainen, J. Prodrugs: Design and clinical applica-
tions. Nat. Rev. Drug Discovery 2008, 7, 255–270.
(35) Stella, V. J.; Nti-Addae, K. W. Prodrug strategies to overcome
poor water solubility. Adv. Drug Delivery Rev. 2007, 59, 677–694.
(36) Ettmayer, P.; Amidon, G. L.; Clement, B.; Testa, B. Lessons
learned from marketed and investigational prodrugs. J. Med.
Chem. 2004, 47, 2393–2404.
€
€
(37) Sauer, R.; Maurinsh, J.; Reith, U.; Fulle, F.; Klotz, K.-N.; Muller,
C. E. Water-soluble phosphate prodrugs of 1-propargyl-8-styryl-
xanthine derivatives, A2A-selective adenosine receptor antagonists.
J. Med. Chem. 2000, 43, 440–448.
€
€
(16) Mantri, M.; de Graaf, O.; van Veldhoven, J.; Goblios, A.; von
€
Frijtag Drabbe Kunzel, J.; Mulder-Krieger, T.; Link, R.; de Vries,
(38) Gomes, P.; Santos, M. I.; Trigo, M. J.; Castanheiro, R.; Moreira, R.
Improved synthesis of amino acid and dipeptide chloromethyl esters
using bromochloromethane. Synth. Commun. 2003, 33, 1683–1693.
(39) Krise, J. P.; Zygmunt, J.; Georg, G. I.; Stella, V. J. Novel prodrug
approach for tertiary amines: Synthesis and preliminary evalua-
tion of n-phosphonooxymethyl prodrugs. J. Med. Chem. 1999, 42,
3094–3100.
(40) Varia, S.; Stella, V. J. Phenytoin prodrugs V: In vivo evaluation of
some water-soluble phenytoin prodrugs in dogs. J. Pharm. Sci.
2010, 73, 1080–1087.
H.; Beukers, M. W.; Breussee, J.; IJzerman, A. P. 2-Amino-6-furan-
2-y-4-substituted nicotinonitriles as A2A adenosine receptor antago-
nists. J. Med. Chem. 2008, 51, 4449–4455.
(17) Lanier, M. C.; Moorjani, M.; Luo, Z.; Chen, Y.; Lin, E.; Tellew,
J. E.; Zhang, X.; Williams, J. P.; Gross, R. S.; Lechner, S. M.;
Markison, S.; Joswig, T.; Kargo, W.; Piercey, J.; Santos, M.;
Malany, S.; Zhao, M.; Petroski, R.; Crespo, M. I.; Dias, J.-L.;
Saunders, J.; Wen, J.; O’Brien, Z.; Jalali, K.; Madan, A.; Slee, D. H.
N-[6-Amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A re-
ceptor antagonists with improved drug like properties and in vivo
efficacy. J. Med. Chem. 2009, 52, 709–717.
€
(41) Hockemeyer, J.; Burbiel, J. C.; Muller, C. E. Multigram-scale syn-
theses, stability, and photoreactions of A2A adenosine receptor