%0 Journal Article %1 Sauer2000 %A Sauer, R. %A Maurinsh, J. %A Reith, U. %A Fulle, F. %A Klotz, K. N. %A Muller, C. E. %D 2000 %J J Med Chem %K & A2A Adenosine Animals Assay CHO Caudate Cerebral Corpus Cortex/metabolism Cricetinae Humans Nucleus/metabolism P1/*antagonists Prodrugs/*chemical Proteins/antagonists Purinergic Radioligand Rats Recombinant Relationship Solubility Striatum/metabolism Structure-Activity Xanthines/*chemical inhibitors synthesis/chemistry/metabolism/pharmacology synthesis/chemistry/pharmacology Receptor Cell %N 3 %P 440-8 %T Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A(2A)-selective adenosine receptor antagonists %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10669571 %V 43 %X Water-soluble prodrugs of potent, A(2A)-selective adenosine receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3, 7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxystyryl)xanthine derivative (MS-DMPX, 5b) were used as starting points. It was found that polar functional groups suitable for the attachment of a prodrug moiety were tolerated on the styryl ring and even better on the 3-substituent. 8-(m-Hydroxystyryl)-DMPX (7) and 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-1-propargylxanthine (5e, MSX-2) were the most potent and A(2A)-selective compounds and were selected for prodrug formation. For the preparation of 5e a new ring-closure method was applied. Treatment of 6-amino-1-(3-hydroxypropyl)-5-(m-methoxycinnamoylamino)-3-propa rgylur acil with hexamethyldisilazane at high temperature resulted in higher yields of the target xanthine than the standard ring-closure procedure using sodium hydroxide. Phosphate prodrugs were prepared by classical phosphorylation using phosphorus oxychloride and alternatively by using a phosphoramidite method. Phosphates of the aliphatic alcohol 5e could be obtained by both methods in similar yields. The phenolic compound 7, however, could be phosphorylated only by using the phosphoramidite method. The disodium salts of the phosphate prodrugs exhibited high water solubility (8-(m-methoxystyryl)-7-methyl-3-3-O-phosphatylpropyl-1- propargylxan thine disodium salt, 9b: 17 mM, 9 mg/mL). Prodrug 9b was found to be stable in aqueous solution (pH 7) but readily cleaved by phosphatases to liberate 5e (MSX-2). Compound 5e showed high affinity for rat A(2A) AR (K(i) = 8 nM), human recombinant A(2A) AR (K(i) = 5 nM), and human native A(2A) AR (K(i) = 15 nM) and was highly selective versus rat A(1) AR (110-fold), human recombinant A(2A) AR (500-fold), human A(2B) AR (>2000-fold), and human A(3) AR (>2000-fold).

@article{Sauer2000, abstract = {Water-soluble prodrugs of potent, A(2A)-selective adenosine receptor (AR) antagonists were prepared. 8-(m-Bromostyryl)-3, 7-dimethyl-1-propargylxanthine (BS-DMPX, 11) and the analogous 8-(m-methoxystyryl)xanthine derivative (MS-DMPX, 5b) were used as starting points. It was found that polar functional groups suitable for the attachment of a prodrug moiety were tolerated on the styryl ring and even better on the 3-substituent. 8-(m-Hydroxystyryl)-DMPX (7) and 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-1-propargylxanthine (5e, MSX-2) were the most potent and A(2A)-selective compounds and were selected for prodrug formation. For the preparation of 5e a new ring-closure method was applied. Treatment of 6-amino-1-(3-hydroxypropyl)-5-(m-methoxycinnamoylamino)-3-propa rgylur acil with hexamethyldisilazane at high temperature resulted in higher yields of the target xanthine than the standard ring-closure procedure using sodium hydroxide. Phosphate prodrugs were prepared by classical phosphorylation using phosphorus oxychloride and alternatively by using a phosphoramidite method. Phosphates of the aliphatic alcohol 5e could be obtained by both methods in similar yields. The phenolic compound 7, however, could be phosphorylated only by using the phosphoramidite method. The disodium salts of the phosphate prodrugs exhibited high water solubility (8-(m-methoxystyryl)-7-methyl-3-[3-O-phosphatylpropyl]-1- propargylxan thine disodium salt, 9b: 17 mM, 9 mg/mL). Prodrug 9b was found to be stable in aqueous solution (pH 7) but readily cleaved by phosphatases to liberate 5e (MSX-2). Compound 5e showed high affinity for rat A(2A) AR (K(i) = 8 nM), human recombinant A(2A) AR (K(i) = 5 nM), and human native A(2A) AR (K(i) = 15 nM) and was highly selective versus rat A(1) AR (110-fold), human recombinant A(2A) AR (500-fold), human A(2B) AR (>2000-fold), and human A(3) AR (>2000-fold).}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Sauer, R. and Maurinsh, J. and Reith, U. and Fulle, F. and Klotz, K. N. and Muller, C. E.}, biburl = {https://www.bibsonomy.org/bibtex/2469ba779fe1f4d39d23940cc7988858b/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {1c9542983c717221815bb2170ffe6c15}, intrahash = {469ba779fe1f4d39d23940cc7988858b}, issn = {0022-2623 (Print) 0022-2623 (Linking)}, journal = {J Med Chem}, keywords = {& A2A Adenosine Animals Assay CHO Caudate Cerebral Corpus Cortex/metabolism Cricetinae Humans Nucleus/metabolism P1/*antagonists Prodrugs/*chemical Proteins/antagonists Purinergic Radioligand Rats Recombinant Relationship Solubility Striatum/metabolism Structure-Activity Xanthines/*chemical inhibitors synthesis/chemistry/metabolism/pharmacology synthesis/chemistry/pharmacology Receptor Cell}, month = {Feb 10}, note = {Sauer, R Maurinsh, J Reith, U Fulle, F Klotz, K N Muller, C E In Vitro Research Support, Non-U.S. Gov't United states Journal of medicinal chemistry J Med Chem. 2000 Feb 10;43(3):440-8.}, number = 3, pages = {440-8}, shorttitle = {Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A(2A)-selective adenosine receptor antagonists}, timestamp = {2010-12-14T18:20:40.000+0100}, title = {Water-soluble phosphate prodrugs of 1-propargyl-8-styrylxanthine derivatives, A(2A)-selective adenosine receptor antagonists}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10669571}, volume = 43, year = 2000 }