In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

Development of 1,4-benzodiazepine cholecystokinin type B antagonists.

A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is L-365,260, a compound which has been submitted for clinical evaluation. Details of the ability to modulate the receptor interactions of these benzodiazepines by appropriate structure modifications are discussed which imply the possibility of further refining the CCK-B receptor affinity and selectivity of this class of compounds.

Nanomolar-affinity, non-peptide oxytocin receptor antagonists.

Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.

Orally active, nonpeptide oxytocin antagonists.

The first nonpeptide antagonists of the neurohypophyseal hormone, oxytocin (OT) are described. Derivatives of the spiroindenepiperidine ring system, these compounds include L-366,509, an orally bioavailable OT antagonist with good in vivo duration. The potential use of these agents for treatment of preterm labor and their significance as new nonpeptide ligands for peptide receptors are discussed.

Cholecystokinin-A receptor ligands based on the kappa-opioid agonist tifluadom.

Tifluadom, a kappa-opioid agonist and cholecystokinin-A (CCK-A) receptor antagonist, was utilized as a model to prepare a series of 2-(aminomethyl)- and 3-(aminomethyl)-1,4-benzodiazepines. These compounds were tested in vitro as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. All compounds with IC50's less than 100 microM proved to have greater affinity for the CCK-A receptor, with the most potent analogue, 6e, having an IC50 of 0.16 microM. The benzodiazepines described in this study are simultaneously CCK-A and opioid receptor ligands. The ramification of this dichotomy on current concepts of peptide hormone action are discussed. These results further demonstrate the versatility of the benzodiazepine core structure for designing nonpeptide ligands for peptide receptors and the ability to fine-tune the receptor interactions of these benzodiazepines by appropriate structure modifications.

Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists.

3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.

Renin inhibitors containing hydrophilic groups. Tetrapeptides with enhanced aqueous solubility and nanomolar potency.

Nineteen tetrapeptides containing statine (Sta) and 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) were prepared. Solubility measurements of these compounds were carried out in H2O and in pH 7.4 phosphate buffer solution, and their partition coefficients were determined in a 1:1 1-octanol/sodium phosphate-citric acid buffer system. The tetrapeptides were tested in vitro for their ability to inhibit porcine, canine, and human plasma renins. Four compounds, 6, 12, 14, and 20, were potent inhibitors against all renins tested (IC50 = 10(-9) M). Compound 12 was administered orally to dogs and substantially inhibited plasma renin activity for up to 5 h. The addition of polar groups to the C-terminus of Sta- and ACHPA-containing tetrapeptides renders them soluble in aqueous milieu and provides a valuable tool with which to examine the role of the renin-angiotensin system in physiological and pathological circumstances.

Cholecystokinin antagonists. Synthesis and biological evaluation of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines.

A series of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines was prepared by standard methodology. These compounds were tested in vitro as antagonists of the binding of [125I]cholecystokinin (CCK) to rat pancreas and guinea pig brain receptors and of the binding of [125I]gastrin to guinea pig gastric glands. All compounds proved to have greater affinity for the peripheral CCK receptor with some analogues having IC50's in the subnanomolar range. In vivo activity of selected compounds in mice is presented and the structure/activity profile of this class of benzodiazepines as CCK antagonists is discussed.

Renin inhibitors. Statine-containing tetrapeptides with varied hydrophobic carboxy termini.

A series of statine-containing tetrapeptides, systematically modified at the carboxy terminus with various hydrophobic aromatic groups, is described. These compounds were tested in vitro for their ability to inhibit porcine, human plasma, and purified human kidney renins. These analogues help to define optimal binding aspects in a region of the enzyme that appears to be specific for spatial arrangement of aromatic groups. Replacement of the metabolically labile Phe amide with nonpeptidal groups proved possible while achieving inhibitory potency in the nanomolar range vs. porcine kidney renin. For the compounds 6i, 6m, and 6o, a large discrepancy in potency between the human plasma and the purified human kidney renin assays was observed. This disparity does not appear to be a consequence of a previously proposed plasma binding component.

Design of nonpeptidal ligands for a peptide receptor: cholecystokinin antagonists.

A series of 3-substituted 5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), have been synthesized. Designed on the basis of facts regarding CCK, its natural-product antagonist asperlicin (3), and the antianxiety agent diazepam (4), these compounds represent a significant departure from existing CCK antagonists. They also constitute perhaps the first examples of simple, nonpeptidal ligands for a peptide receptor to arise by design rather than by screening. These compounds serve to illuminate the distinction between central and peripheral CCK receptors, as well as to provide orally effective CCK antagonists of potential pharmacological or therapeutic utility. One rationale for their receptor affinity has possible applications in the design of nonpeptidal ligands for other receptors, peptidal as well as nonpeptidal.

Cholecystokinin antagonists. Synthesis of asperlicin analogues with improved potency and water solubility.

Seventeen analogues of the selective, competitive cholecystokinin (CCK) antagonist asperlicin 1 were prepared. These compounds were tested as inhibitors of the binding of [125I]CCK to rat pancreas and guinea pig brain receptors. Compounds 4, 7, and 8 were more potent than asperlicin on the pancreatic CCK receptor. One analogue, 17, displayed potency equivalent to asperlicin on the pancreas CCK receptor and showed a marked improvement in aqueous solubility, thereby facilitating the use of this class of CCK antagonists in physiological and pharmacological studies.

Design of potent, orally effective, nonpeptidal antagonists of the peptide hormone cholecystokinin.

We describe the design and synthesis of nonpeptidal antagonists of the peptide hormone cholecystokinin. Several of these compounds have high specificity and nanomolar binding affinity and are active after oral administration. To our knowledge, the design of such agents has not previously been accomplished for any peptide hormone. The structural similarities between these synthetic compounds and the anxiolytic 1,4-benzodiazepines are noted, and the potential of this structural feature for future design of ligands for other peptide hormone receptors is discussed.

(+)- and (-)-3-Methoxycyproheptadine. A comparative evaluation of the antiserotonin, antihistaminic, anticholinergic, and orexigenic properties with cyproheptadine.

The synthesis and resolution of (+/-)-3-methoxycyproheptadine [(+/-)-4] are described. As a peripheral serotonin antagonist, (+/-)-4 was found to be one-half as potent as cyproheptadine (1b). The peripheral anticholinergic and antihistaminic activities as well as the orexigenic property of (+/-)-4 are less than those of 1b. A further comparison of the enantiomers (+)-4 and (-)-4 shows that all of the anticholinergic activity of (+/-)-4 resides solely in the dextrorotatory enantiomer, (+)-4, while the antiserotonin activity, which is similar to that of 1b, resides in the levorotatory enantiomer, (-)-4. Antihistaminic and orexigenic activity also resides in (-)-4 but these properties are reduced compared to those of 1b.

Synthesis and stereospecific antipsychotic activity of (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.

The synthesis and resolution of 3-iodocyproheptadine [(+/-)-5a] and 1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine [(+/-)-5b] are described. The resulting atropisomers undergo reaction with trifluoromethylthiocopper to give optically active products without extensive racemization. In this manner, optically pure (+)- and (-)-3-trifluoromethylthiocyproheptadine [(+)-6a and (-)-6a, respectively] and (+)- and (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(+)-6b and (-)-6b, respectively] have been prepared. The influence of a chiral europium shift reagent on the proton and fluorine resonance signals as a diagnostic tool for the determination of the optical purities of these atropisomers is discussed. The four compounds, (+)-6a, (-)-6a, (+)-6b, and (-)-6b, were studied in squirrel monkeys for their ability to block conditioned avoidance responding. All of the antiavoidance activity was found to reside solely in the levorotatory compounds (-)-6a and (-)-6b. Further comparison of the enantiomers (-)-6b and (+)-6b showed that the ability to antagonize apomorphine-induced stereotyped behavior is confined to the levorotatory isomer (-)-6b while weak central anticholinergic activity resides solely in the dextrorotatory isomer (+)-6b. Neither (-)-6b has significant peripheral anticholinergic activity.

A comparison of the antiserotonin, antihistamine, and anticholinergic activity of cyproheptadine with analogues having furan nuclei fused to the 10,11-vinylene bridge.

A series of cyproheptadine derivatives having furan nuclei fused to the 10,11-vinylene bridge has been prepared. None of the compounds retain the potent antiserotonin and antihistaminic actions of cyproheptadine. 1-methyl-4-(1-methyl-8H-dibenzo[a,e]furo[3,4-c]cyclohepten-8-ylidene)piperidine (7), 1-methyl-4-(1,3-dihydro-1-oxo-8H-[3,4:6,7]cycloheptal[1,2-c]furan-8-ylidene)piperidine (10), and its reduction product 11 retained the peripheral anticholinergic activity of cyproheptadine.