Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties

作者：Romeiro Luiz A S; Ferreira Marcos da Silva; da Silva Leandro L; Castro Helena C; Miranda Ana L P; Silva Claudia L M; Noel Francois; Nascimento Jessica B; Araujo Claudia V; Tibirica Eduardo; Barreiro Eliezer J; Fraga Carlos A M^*

来源：European Journal of Medicinal Chemistry, 2011, 46(7): 3000-3012.

DOI：10.1016/j.ejmech.2011.04.032

• N-Phenylpiperazine
• Alpha-adrenoceptor antagonist
• Benign prostatic hyperplasia
• Safrole, 1,3-Benzodioxole

We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl)-4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [(3)H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (K(i) = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (K(B) = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (K(B) = 0.017 nM).

• 出版日期2011-7