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 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.
Roche Bioscience, 3431 Hillview Ave, Palo Alto, CA 94304, USA. francisco.lopez-tapia@roche.com
F J
FJ
Lopez
L
L
Arias
R
R
Chan
D E
DE
Clarke
T R
TR
Elworthy
A P D W
AP
Ford
A
A
Guzman
S
S
Jaime-Figueroa
J R
JR
Jasper
D J
DJ
Morgans
F
F
Padilla
A
A
Perez-Medrano
C
C
Quintero
M
M
Romero
L
L
Sandoval
S A
SA
Smith
T J
TJ
Williams
D R
DR
Blue
D000284:Administration, Oral; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001682:Biological Availability; D004285:Dogs; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D014498:Uracil / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*
C547713:ADRA1A protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D014498:Uracil