A systematic modification of the caffeinyl core and substituents of the ref. compd. (E)-8-(3-chlorostyryl)caffeine led to the 9- deazaxanthine deriv. (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1Hpyrrolo[ 3,2-d]pyrimidine-2,4-(3H,5H)-dione (I), which acts as a dual human A2a antagonist/MAO-B inhibitor (Ki(A2A) = 260 nM; IC50(MAO-B) = 200 nM; IC50(MAO-A) = 10 mM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compd. is the best balanced A2A antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti- Parkinson's agents. A no. of analogs of I were synthesized and qual. SARs are discussed. Two analogs of I, namely II and III, inhibit MAO-B with IC50 of 68 and 48 nM, resp., being 5-7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC50 = 334 nM).
Rivara S, Piersanti G, Bartoccini F, Diamantini G, Pala D, Riccioni T, et al. (2013). Synthesis of (E)-8-(3-Chlorostyryl)caffeine Analogues Leading to 9-Deazaxanthine Derivatives as Dual A2A Antagonists/MAO-B Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 56(3), 1247-1261 [10.1021/jm301686s].
Synthesis of (E)-8-(3-Chlorostyryl)caffeine Analogues Leading to 9-Deazaxanthine Derivatives as Dual A2A Antagonists/MAO-B Inhibitors
Cabri W;
2013
Abstract
A systematic modification of the caffeinyl core and substituents of the ref. compd. (E)-8-(3-chlorostyryl)caffeine led to the 9- deazaxanthine deriv. (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1Hpyrrolo[ 3,2-d]pyrimidine-2,4-(3H,5H)-dione (I), which acts as a dual human A2a antagonist/MAO-B inhibitor (Ki(A2A) = 260 nM; IC50(MAO-B) = 200 nM; IC50(MAO-A) = 10 mM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compd. is the best balanced A2A antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti- Parkinson's agents. A no. of analogs of I were synthesized and qual. SARs are discussed. Two analogs of I, namely II and III, inhibit MAO-B with IC50 of 68 and 48 nM, resp., being 5-7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC50 = 334 nM).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
