Design and synthesis of novel alpha1a adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia.
We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects.
Nagarathnam
D
D
Departments of Chemistry, Pharmacology, and Pharmaceutical Operations, Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652, USA.
Wetzel
J M
JM
Miao
S W
SW
Marzabadi
M R
MR
Chiu
G
G
Wong
W C
WC
Hong
X
X
Fang
J
J
Forray
C
C
Branchek
T A
TA
Heydorn
W E
WE
Chang
R S
RS
Broten
T
T
Schorn
T W
TW
Gluchowski
C
C
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011470:Prostatic Hyperplasia / Q000188:drug therapy*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D004095:Dihydropyridines; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; D011994:Recombinant Proteins; C116545:SNAP 5540