3476 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 18
Knutsen et al.
(33) Schubert, P.; Rudolphi, K. A.; Fredholm, B. B.; Nakamura, Y.
Modulation of nerve and glial function by adenosine - role in
the development of ischemic damage. Int. J . Biochem. 1994, 26,
1227-1236.
(34) Cronstein, B. N. Adenosine, an endogenous antiinflammatory
agent. J . Appl. Physiol. 1994, 76, 5-13.
(35) Ramkumar, V.; Nie, Z.; Rybak, L. P.; Maggirwar, S. B. Adenos-
ine, antioxidant enzymes and cytoprotection. TIPS 1995, 16,
283-285.
(50) Siddiqi, S. M.; J acobson, K. A.; Esker, J . L.; Olah, M. E.; Li, X.-
d.; Melman, N.; Tiwari, K. N.; Secrist, J . A., III; Schneller, S.;
Cristalli, G.; Stiles, G. L.; J ohnson, C. R.; IJ zerman, A. P. Search
for new purine- and ribose-modified adenosine analogues as
selective agonists and antagonists at adenosine receptors. J .
Med. Chem. 1995, 38, 1174-1178.
(51) Schaumann, E.; Sclierf, G.; Pfleiderer, T.; Weber, E. The effect
of administering repeated doses of phenyl-isopropyl-adenosine
on fat and carbohydrate metabolism in healthy, fasted human
volunteers. Drug Res. 1972, 22, 593-596.
(36) Soricelli, A.; Postiglione, A.; Cuocolo, A.; De Chiara, S.; Ruocco,
A.; Brunetti, A.; Salvatore, M.; Ell, P. J . Effect of adenosine on
cerebral blood flow as evaluated by single-photon emission
computed tomography in normal subjects and in patients with
occlusive carotid disease. Stroke 1995, 26, 1572-1576.
(37) Knutsen, L. J . S.; Sheardown, M. J .; Roberts, S. M.; Mogensen,
J . P.; Olsen, U. B.; Thomsen, C.; Bowler, A. N. Adenosine A1
and A3 selective N-alkoxypurines as novel cytokine modulators
and neuroprotectants. Drug Dev. Res. 1999, 45, 214-221.
(38) Feuerstein, G. Z.; Wang, X.; Barone, F. C. Inflammatory gene
expression in cerebral ischemia and trauma: potential new
therapeutic targets. Ann. N. Y. Acad. Sci. 1997, 825, 179-193.
(39) Mullane, K. M.; Williams, M. Adenosine and cardiovascular
function. In Adenosine and Adenosine Receptors; Williams, M.,
Ed.; Humana Press Inc.: Clifton, NJ , 1990; pp 289-333.
Shryock, J . C.; Belardinelli, L. Adenosine and adenosine recep-
tors in the cardiovascular system: biochemistry, physiology, and
pharmacology. Am. J . Cardiol. 1997, 79, 2-10. Olsson, R. A.
Adenosine receptors in the cardiovascular system. Drug Dev.
Res. 1997, 39, 301-307. Collis, M. G. Effect of adenosine on the
coronary circulation. In Adenosine and Adenosine Nucleotides
as Regulators of Cellular Function; Phillis, J . W., Ed.; CRC
Press: Boca Raton, FL, 1991; pp 171-180.
(40) Fozard, J . R.; Menninger, K.; Tapparelli, C. Cardiovascular and
metabolic effects of SDZ WAG-994, a selective adenosine A1
receptor agonist, after acute and chronic dosing in the rhesus
monkey. Br. J . Pharmacol. 1994, 112, U69. Wagner, H.; Milavec-
Krizman, M.; Gadient, F.; Menninger, C.; Schoeffter, P.; Tap-
parelli, C.; Pfannkuche, H.-J .; Fozard, J . R. General pharma-
cology of SDZ WAG 944, a potent selective and orally active
adenosine A1 agonist. Drug Dev. Res. 1995, 34, 276-288.
Belardinelli, L.; Lu, J .; Dennis, D.; Martens, J .; Shryock, J . C.
The cardiac effects of a novel A1-adenosine receptor agonist in
guinea pig isolated heart. J . Pharmacol. Exp. Ther. 1994, 271,
1371-1382. Cox, B. F.; Clark, K. L.; Perrone, M. H.; Welzel, G.
E.; Greenland, B. D.; Colussi, D. J .; Merkel, L. A. Cardiovascular
and metabolic effects of adenosine A1-receptor agonists in
streptozotocin-treated rats. J . Cardiovasc. Pharmacol. 1997, 29,
417-426. Ishikawa, J .; Mitani, H.; Bandoh, T.; Kimura, M.;
Totsuka, T.; Hayashi, S. Hypoglycemic and hypotensive effects
of 6-cyclohexyl-2′-O-methyl-adenosine, an adenosine A1 receptor
agonist, in spontaneously hypertensive rat complicated with
hyperglycemia. Diabetes Res. Clin. Pract. 1998, 39, 3-9.
(41) Ueeda, M.; Thompson, R. D.; Padgett, W. L.; Secunda, S.; Daly,
J . W.; Olsson, R. A. Cardiovascular actions of adenosines, but
not adenosine receptors, differ in rat and guinea pig. Life Sci.
1991, 49, 1351-1358.
(52) Irshad, F.; Dagenais, G. R.; Fedor, E. J .; Cavanaugh, J . H. Trials
with an adenosine analogue as antianginal medication. Clin.
Pharmacol. Ther. 1977, 22, 470-474.
(53) Bertolet, B. D.; Anand, I. S.; Bryg, R. J .; Mohanty, P. K.;
Chatterjee, K.; Cohn, J . N.; Khurmi, N. S.; Pepine, C. J . Effects
of A1 adenosine receptor agonism using N6-cyclohexyl-2′-O-
methyladenosine in patients with left ventricular dysfunction.
Circulation 1996, 94, 1212-1215.
(54) Knutsen, L. J . S.; Lau, J . Purine derivatives. Novo Nordisk A/S,
WO 93/23418, Nov 25, 1993.
(55) Lau, J .; Knutsen, L. J . S.; Sheardown, M. J .; Hansen, A. J . Purine
derivatives. Novo Nordisk A/S, WO 94/14832, J uly 7, 1994.
(56) Lau, J .; Knutsen, L. J . S. Purine derivatives. Novo Nordisk A/S,
WO 95/07921, Mar 23, 1995.
(57) Robins, M. J .; Uznanski, B. Improved acetylation and deoxy-
genative chlorination of guanosine; nonaqueous diazotisation-
dediazotisation of a 2-aminopurine nucleoside. In Nucleic Acid
Chemistry; Townsend, L. B., II., Tipson, R. S., Eds.; J ohn Wiley
and Sons: New York 1986; Vol. 3, pp 144-148.
(58) Mitsunobu, O. The use of diethyl azocarboxylate and triph-
enylphosphine in synthesis and transformation of natural
products. Synthesis 1981, 1-28.
(59) Knutsen, L. J . S.; Lau, J . C2,N6-Disubstituted adenosine deriva-
tives. U.S. 5,432,164, J uly 11, 1995. Knutsen, L. J . S.; Lau, J .
2-Chloro-N6-substituted adenosines, their pharmaceutical com-
positions and activity in treating ischemias. U.S. 5,430,027, J uly
4, 1995.
(60) Borchardt, R. T.; Huber, J . A.; Wu, Y. S. Convenient preparation
of S-adenosylhomocysteine and related compounds. J . Org.
Chem. 1976, 41, 565-567. See also: Taylor, M. D.; Moos, W.
M.; Hamilton, H. M.; Szotek, D. S.; Patt, W. C.; Badger, E. W.;
Bristol, J . A.; Bruns, R. F.; Heffner, T. G.; Mertz, T. G. Ribose-
modified adenosine analogues as adenosine receptor agonists.
J . Med. Chem. 1986, 29, 346-353.
(61) Gurden, M. F.; Coates, J .; Ellis, F.; Evans, B.; Foster, M.; Hornby,
E.; Kennedy, I.; Martin, D. P.; Strong, P.; Vardey, C. J .;
Wheeldon, A. Functional characterization of three adenosine
receptor types. Br. J . Pharmacol. 1993, 109, 693-698. Merkel,
L. A.; Hawkins, E. D.; Colussi, D. J .; Greenland, B. D.; Smits,
G. J .; Perrone, M. H.; Cox, B. F. Cardiovascular and antilipolytic
effects of the adenosine agonist GR 79236. Pharmacology 1995,
51, 224-236. Thompson, C. S.; Strong, P.; Mikhailidis, D. P.
Triacylglycerol lowering properties of the adenosine analogue
GR 79236 during 5 days of dosing large, old rats: a pilot study.
Nutr. Res. 1996, 16, 1925-1932.
(62) Evans, B. 2,N-6-Disubstituted adenosines and their antihyper-
tensive methods of use. U.S. 5,032,583, J uly 16, 1991.
(63) Gadient, F.; Milavec, M.; Muller, E. New use of organic com-
pounds. Sandoz Ltd., European Patent Application 0 490 818
A1, J une 17, 1992.
(64) Gadient, F.; Mangold, B. M.; Fozard, J . R.; Prashad, M.; Kapa,
P. K. Adenosine derivatives. Sandoz Ltd., WO 95/30683, Nov
16, 1995.
(42) Martin, P. Evidence that adenosine receptors in the dog left
atrium are not of the typical A1 or A2 adenosine receptor
subtypes. Eur. J . Pharmacol. 1992, 214, 199-205.
(43) Barraco, R. A.; Phillis, J . W. Subtypes of adenosine receptors in
the brainstem mediate opposite blood pressure changes. Neu-
ropharmacology 1991, 30, 403-407.
(44) Barraco, R. A.; Aggarwal, A. K.; Phillis, J . W.; Moron, M. A.;
Wu, P. H. Dissociation of the locomotor and hypotensive effects
of adenosine analogues in the rat. Neurosci. Lett. 1984, 48, 139-
144.
(45) White, P. J .; Rose´ Meyer, R. B.; Hope, W. Functional charac-
terization of adenosine receptors in the nucleus tractus solaritus
mediating hypotensive responses in the rat. Br. J . Pharmacol.
1996, 117, 305-308.
(65) Gerwins, P.; Norstedt, C.; Fredholm, B. B. Characterization of
adenosine A1 receptors in intact DDT1 MF2 smooth muscle cells.
Mol. Pharmacol. 1990, 38, 660-666.
(66) J acobson, K. A.; Nikodijevic, O.; J i, X.-d.; Berkich, D. A.; Eveleth,
D.; Dean, R. L.; Hiramatsu, K.-I.; Kassel, N. F.; Van Galen, P.
J . M.; Lee, K. S.; Bartus, R. T.; Daly, J . W.; LaNoue, K. F.;
Maillard, M. Synthesis and biological activity of N6-(p-sulfophe-
nyl)alkyl and N6-sulfoalkyl derivatives of adenosine: water-
soluble and peripherally selective adenosine agonists. J . Med.
Chem. 1992, 35, 4143-4149. Van Schaick, E. A.; De Greef, H.
J . M. M.; Langemeijer, M. W. E.; Sheehan, M. J .; Ijzerman, A.
P.; Danhof, M. Pharmacokinetic-pharmacodynamic modeling of
the anti-lipolytic and anti-ketotic effects of the adenosine A1-
receptor agonist N6-(p-sulfophenyl)adenosine in rats. Br. J .
Pharmacol. 1997, 122, 525-533. Van Schaick, E. A.; Zuideveld,
K. P.; Tukker, H. E.; Langemeijer, M. W. E.; Ijzerman, A. P.;
Danhof, M. Metabolic and cardiovascular effects of the adenosine
A1 receptor agonist N6-(p-sulfophenyl)adenosine in diabetic
Zucker rats: influence of the disease on the selectivity of action.
J . Pharmacol. Exp. Ther. 1998, 287, 21-30.
(46) Cornfield, L. J .; Hu, S.; Hurt, S. D.; Sillis M. A. 3H-2-Pheny-
laminoadenosine (3H-CV 1808) labels a novel adenosine receptor
in rat brain. J . Pharmacol. Exp. Ther. 1992, 263, 552-561.
(47) Born, G. V. R.; Haslam, R. J .; Goldman, M.; Lowe, R. D.
Comparative effectiveness of adenosine analogues as inhibitors
of blood-platelet aggregation and as vasodilators in man. Nature
1965, 205, 678-680.
(48) Schaumann, E.; Kutscha, W. Clinical-pharmacological studies
with a new orally active adenosine derivative. Drug Res. 1972,
22, 783-790.
(67) Nikodijevic, O.; Sarges, R.; Daly, J . W.; J acobson, K. A. Behav-
ioral effects of A1 and A2-selective adenosine agonists and
antagonists: evidence for synergism and antagonism. J . Phar-
macol. Exp. Ther. 1991, 259, 286-294.
(49) Klitgaard, H.; Knutsen, L. J . S.; Thomsen, C. Contrasting effects
of adenosine A1 and A2 receptor ligands in different chemocon-
vulsive models. Eur. J . Pharmacol. 1993, 224, 221-228.