Theodore P. Broten

Design and Synthesis of Novel α1a Adrenoceptor-Selective Dihydropyridine Antagonists for the Treatment of Benign Prostatic Hyperplasia

We report the synthesis and evaluation of novel α1a 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 α1a 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 ...

Selective α1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones

A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.

3-(1-Piperazinyl)-4,5-dihydro-1H-benzo[g]indazoles: high affinity ligands for the human dopamine D4 receptor with improved selectivity over ion channels

3-(4-Piperidinyl)-5-arylpyrazoles, such as 1, were selective for the cloned human dopamine D4 receptor (hD4), but also showed affinity at voltage sensitive calcium, sodium and potassium ion channels. A combination of substituent changes to reduce the basicity of the piperidine nitrogen and conformational restriction to give 4,5-dihydro-1H-benzo[g]indazoles reduced this ion channel affinity at the expense of selectivity for hD4 over other dopamine receptors. Incorporation of piperazine into the 4,5-dihydro-1H-benzo[g]indazoles in place of piperidine gave a novel series of high affinity, selective, orally bioavailable hD4 ligands, such as 16, with improved selectivity over ion channels.

In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for angiotensin AT2 receptors

Abstract L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[(2′-(N-(3-methyl-1-butoxy)carbonylaminosulfonyl)[1,1′]-biphenyl-4-yl]-methyl]-3H-imidazo-[4,5-b] is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.

Pharmacology of losartan, an angiotensin II receptor antagonist, in animal models of hypertension

Background: Clinical experience with angiotensin converting enzyme (ACE) inhibitors has shown that inhibition of the renin–angiotensin system is effective therapy for hypertension and heart failure. Losartan (DuP753, MK954, cozaar) is the first non-peptidic drug that inhibits the renin-angiotensin system by selectively blocking the interaction of angiotensin II with its receptor Differences between losartan and ACE inhibitors: Pharmacological differences between ACE inhibitors and losartan could affect comparative efficacy and/or safety. In addition to angiotensin I, ACE has other substrates (e.g. kinins). Blocking the metabolism of kinins with ACE inhibitors could be beneficial (e.g. vasodilation) and/or elicit side effects (e.g. cough) which will not be produced by losartan. Non-ACE pathways of angiotensin II formation have been described (e.g. angiotensin I convertase) which may limit the ability of ACE inhibitors to prevent formation of angiotensin II in all tissues. Losartan blocks angiotensin II responses irrespective of the route or site of angiotensin II formation. Two binding sites for angiotensin II are widely accepted, AT1 and AT2. Losartan blocks only AT1 sites while ACE inhibitors functionally block angiotensin II interaction with both sites. Since the physiological role for AT2 sites is unknown, the relevance of this difference between ACE inhibitors and losartan is questionable Hypertension: In animal models of hypertension, the efficacy of losartan is equivalent to the efficacy of ACE inhibitors. In animal models that reflect complications of hypertension, such as kidney dysfunction, cardiac and vascular hypertrophy and stroke, losartan and ACE inhibitors are also equally effective. From these results, kinin potentiation and lack of inhibition of angiotensin I convertase do not lead to differences in pharmacological efficacy between ACE inhibitors and losartan. Therefore, with respect to therapeutic efficacy, results in animal models indicate that losartan will display the beneficial pharmacology of ACE inhibitors without the detrimental side effects attributed to kinin potentiation

Cardiovascular and Renal Review: Pharmacology of Angiotensin II Receptor Antagonists: Comparison with Renin Inhibitors and Angiotensin-Converting Enzyme Inhibitors

Nonpeptide angiotensin II (ANG II) receptor antagonists are a new class of inhibitors of the renin angiotensin system (RAS). Several ANG II receptor antagonists are currently in clinical development for the treatment of hypertension and heart failure. The discovery of these compounds follows many years of research on renin and the spectacular success of angiotensin converting enzyme (ACE) inhibitors, both as therapeutic agents and pharmacological tools. By inhibiting the interaction of ANG II with its receptor(s), studies utilising ANG II receptor antagonists have furthered our understanding of the RAS. This class of compounds may provide an interesting alternative to ACE inhibitors for the clinical management of hypertension and heart failure. The present article examines the comparative preclinical pharmacology of ANG II receptor antagonists, ACE inhibitors and renin inhibitors, with two objectives: 1) to demonstrate how our knowledge of the RAS has been extended utilising these three classes of pharmac...