Chimenti Franco, Bolasco Adriana, Manna Fedele, Secci Daniela, Chimenti Paola, Befani Olivia, Turini Paola, Giovannini Valentina, Mondovì Bruno, Cirilli Roberto, La Torre Francesco
Dipartimento di Studi di Chimica e Tossicologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma La Sapienza, Piazzale A. Moro 5, 00185 Rome, Italy.
J Med Chem. 2004 Apr 8;47(8):2071-4. doi: 10.1021/jm031042b.
A novel series of 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives 1-12 have been synthesized and investigated for the ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The new synthesized compounds 1-12 proved to be more reversible, potent, and selective inhibitors of MAO-A than of MAO-B. Knowing that stereochemistry may be an important modulator of biological activity, we performed the semipreparative chromatographic enantioseparation of the most potent, selective, and chiral compounds, 6 and 11. The separated enantiomers were then submitted to in vitro biological evaluation while increasing their inhibitory activity and A selectivity. The (-)-6 enantiomer shows K(i(MAO-A)) = 2 nM and SI = 165 000, (+)-6 shows K(i(MAO-A)) = 6 nM and SI = 166 666, (-)-11 shows K(i(MAO-A)) = 4 nM and SI = 80 000, and (+)-11 shows K(i(MAO-A)) = 7 nM and SI = 38 571.
合成了一系列新型的1-乙酰基-3-(4-羟基-和2,4-二羟基苯基)-5-苯基-4,5-二氢-(1H)-吡唑衍生物1-12，并研究了它们选择性抑制单胺氧化酶(MAO) A和B同工型活性的能力。新合成的化合物1-12被证明是比MAO-B更具可逆性、强效性和选择性的MAO-A抑制剂。鉴于立体化学可能是生物活性的重要调节剂，我们对最具强效性、选择性和手性的化合物6和11进行了半制备色谱对映体分离。然后对分离得到的对映体进行体外生物学评价，同时提高它们的抑制活性和对A的选择性。(-)-6对映体的K(i(MAO-A)) = 2 nM，选择性指数(SI) = 165000，(+)-6的K(i(MAO-A)) = 6 nM，SI = 166666，(-)-11的K(i(MAO-A)) = 4 nM，SI = 80000，(+)-11的K(i(MAO-A)) = 7 nM，SI = 38571。
