Synthesis, pharmacology and pharmacokinetics of 3-(4-aryl-piperazin-1-ylalkyl)-uracils as uroselective alpha1A-antagonists

Predominance in the urethra and prostate of the alpha(1A)-adrenoceptor subtype, which is believed to be the receptor mediating noradrenaline induced smooth muscle contraction in these tissues, led to the preparation of alpha(1A)-selective antagonists to be tested as uroselective compounds for the tr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2003-06, Vol.13 (11), p.1873-1878
Main Authors: Lopez, F J, Arias, L, Chan, R, Clarke, D E, Elworthy, T R, Ford, A P D W, Guzman, A, Jaime-Figueroa, S, Jasper, J R, Morgans, Jr, D J, Padilla, F, Perez-Medrano, A, Quintero, C, Romero, M, Sandoval, L, Smith, S A, Williams, T J, Blue, D R
Format: Article
Language:English
Subjects:
Administration, Oral
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists - chemical synthesis
Adrenergic alpha-Antagonists - pharmacokinetics
Adrenergic alpha-Antagonists - pharmacology
Animals
Aorta - drug effects
Biological Availability
Dogs
Half-Life
Haplorhini
Humans
Injections, Intravenous
Male
Microsomes, Liver - metabolism
Piperazines - chemical synthesis
Piperazines - chemistry
Piperazines - pharmacokinetics
Piperazines - pharmacology
Rats
Receptors, Adrenergic, alpha-1
Uracil - chemical synthesis
Uracil - chemistry
Uracil - pharmacokinetics
Uracil - pharmacology
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Summary:Predominance in the urethra and prostate of the alpha(1A)-adrenoceptor subtype, which is believed to be the receptor mediating noradrenaline induced smooth muscle contraction in these tissues, led to the preparation of alpha(1A)-selective antagonists to be tested as uroselective compounds for the treatment of benign prostatic hyperplasia. Thus, a number of selective alpha(1A)-adrenoceptor antagonists were synthesized and assayed in vitro for potency and selectivity. Dog pharmacokinetic parameters of 12 (RO700004) and its metabolite 40 (RO1104253) were established. The relative selectivity of intravenously administered 12, 40 and standard prazosin to inhibit hypogastric nerve stimulation-induced increases in intraurethral prostatic pressure versus phenylephrine-induced increases in diastolic blood pressure in anesthetized dogs was 76, 71 and 0.6, respectively.
ISSN:0960-894X