Author: Luciana de Camargo Nascente ; Renata Oliveira Silva ; Laís Flávia Nunes Lemes ; Guilherme D. Brand ; Giulio Vistoli ; Patrícia Coelho do Nascimento Nogueira ; Michela Buccioni ; Gabriella Marucci ; Andressa Souza de Oliveira ; Luiz Antonio Soares Romeiro ; Maria Laura Bolognesi ; Edilberto R. Silveira ; Antonio Cilia ; Elena Poggesi

Arylpiperazines 2-11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.

01 Jul 2011·European Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

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).

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Preclinical	Brazil	Federal University of Rio de Janeiro	01 Jul 2011
Prostatic Hyperplasia	Preclinical	Brazil	Federal University of Rio de Janeiro	01 Jul 2011
Urinary tract obstruction	Preclinical	Brazil	Federal University of Rio de Janeiro	01 Jul 2011
Urination Disorders	Preclinical	Brazil	Federal University of Rio de Janeiro	-

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