Synthesis of (E)-8-(3-chlorostyryl)caffeine analogues leading to 9-deazaxanthine derivatives as dual A(2A) antagonists/MAO-B inhibitors.

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Rivara S, Piersanti G, Bartoccini F, Diamantini G, Pala D, Riccioni T, Stasi MA, Cabri W, Borsini F, Mor M, Tarzia G, Minetti P

Synthesis of (E)-8-(3-chlorostyryl)caffeine analogues leading to 9-deazaxanthine derivatives as dual A(2A) antagonists/MAO-B inhibitors.

J Med Chem. 2013 Feb 14;56(3):1247-61. doi: 10.1021/jm301686s. Epub 2013 Jan 16.

PubMed ID

23281824 [ View in PubMed

]

Abstract

A systematic modification of the caffeinyl core and substituents of the reference compound (E)-8-(3-chlorostyryl)caffeine led to the 9-deazaxanthine derivative (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)-d ione (17f), which acts as a dual human A(2a) antagonist/MAO-B inhibitor (K(i)(A(2A)) = 260 nM; IC(50)(MAO-B) = 200 nM; IC(50)(MAO-A) = 10 muM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A(2A) 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 number of analogues of 17f were synthesized and qualitative SARs are discussed. Two analogues of 17f, namely 18b and 19a, inhibit MAO-B with IC(50) of 68 and 48 nM, respectively, being 5-7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC(50) = 334 nM).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Clorgiline	Amine oxidase [flavin-containing] A	IC 50 (nM)	12	N/A	N/A	Details
Selegiline	Amine oxidase [flavin-containing] B	IC 50 (nM)	334	N/A	N/A	Details