Mol. modeling studies, including the comparative mol. field anal. (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biol. activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A2BAR, a new series of compds. was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (I): Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compds. with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine (II) displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250).
Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)xanthines as Potent and Selective A2B Adenosine Receptor Antagonists
BARALDI, Pier Giovanni;BARALDI, Stefania;SAPONARO, Giulia;PRETI, Delia;ROMAGNOLI, Romeo;PICCAGLI, Laura;VARANI, Katia;BOREA, Pier Andrea;AGHAZADEH TABRIZI, Mojgan
2012
Abstract
Mol. modeling studies, including the comparative mol. field anal. (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biol. activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A2BAR, a new series of compds. was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (I): Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compds. with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine (II) displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250).I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
