N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.
Elworthy
T R
TR
Roche Bioscience, Palo Alto, California 94304-1397, USA.
Ford
A P
AP
Bantle
G W
GW
Morgans
D J
DJ
Ozer
R S
RS
Palmer
W S
WS
Repke
D B
DB
Romero
M
M
Sandoval
L
L
Sjogren
E B
EB
Talamás
F X
FX
Vazquez
A
A
Wu
H
H
Arredondo
N F
NF
Blue
D R
DR
DeSousa
A
A
Gross
L M
LM
Kava
M S
MS
Lesnick
J D
JD
Vimont
R L
RL
Williams
T J
TJ
Zhu
Q M
QM
Pfister
J R
JR
Clarke
D E
DE
D000293:Adolescent; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001667:Binding, Competitive; D006801:Humans; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011224:Prazosin / Q000378:metabolism; D011437:Propylamines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000577:Amides; D010879:Piperazines; D011437:Propylamines; D011224:Prazosin