Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes.

α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.

Chiral analogues of (+)-cyclazosin as potent α1B-adrenoceptor selective antagonist.

(+)-Cyclazosin [(+)-1] is one of most selective antagonists of the α1B-adrenoceptor subtype (selectivity ratios, α1B/α1A = 13, α1B/α1D = 38-39). To improve the selectivity, we synthesized and pharmacologically studied the blocking activity against α1-adrenoceptors of several homochiral analogues of (+)-cyclazosin featuring different substituents on the carbonyl or amine groups, namely (-)-2, (+)-3, (-)-4-(-)-8, (+)-9. Moreover, we studied the activity of some their opposite enantiomers, namely (-)-1, (-)-3, (+)-6, and (-)-9, to evaluate the influence of stereochemistry on selectivity. The benzyloxycarbonyl and methyl (4aS,8aR) analogues (+)-3 and (-)-6 improved in a significant way the α1B selectivity of the progenitor compound: 4 and 14 time vs. the α1D subtype and 35 and 77 times vs. the α1A subtype, respectively. The study confirmed the importance of the hydrophobic cis-octahydroquinoxaline moiety of these molecules for the establishment of interactions with the α1-adrenoceptors as well that of their (4aS,8aR) stereochemistry to grant selectivity for the α1B subtype. Hypotheses on the mode of interaction of these compounds were advanced on the basis of molecular modeling studies performed on compound (+)-3.

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α1A-/α1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α1-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro-N-([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α1A-/α1D-adrenoceptor antagonist (Ki(α1) = 50 nM, EC50(α1A) = 0.8 nM, EC50(α1D) = 1.1 nM), displayed selectivity over α2-adrenoceptors (Ki(α2) = 858 nM), and a 5-fold functional preference over the α1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Clint = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.

Synthesis and evaluation of aporphine analogs containing C1 allyl isosteres at the h5-HT(2A) receptor.

A series of C1 aporphine analogs related to compound 5 and that contain substituted allylic, alkynyl, nitrile, ester and benzyl groups was synthesized and evaluated for affinity at h5HT2A and α1A receptors in functional activity assays that measure calcium release. The presence of branched allylic substituent groups diminished affinity for the h5HT2A receptor. Likewise, the alkynyl, nitrile and ester derivatives evaluated displayed lower 5-HT2A receptor affinity as compared to 5. Hydrophobic, steric and electronic effects impact the affinity of p-substituted benzyl derivatives 8i-8k but in different ways. High hydrophobicity and size favor 5-HT2A affinity whereas, high electronegativity disfavors 5-HT2A affinity. p-Bromobenzyl analog 8k was identified as a 5-HT2A receptor selective ligand, with the highest 5-HT2A receptor affinity of any aporphine known to date. Most of the other analogs were selective for the 5-HT2A versus the α1A receptor. ChemScore binding energies from docking studies correlated qualitatively with the observed trends in affinity for 8i-8k, although the binding energies were not well differentiated quantitatively.

α-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one.

This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for α1- and α2-adrenoceptors were assessed. The compound with highest affinity for the α1-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10 h) with pKi=7.30. Compound with pKi (α1) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α1A- and α1B-adrenoceptors. All compounds tested were antagonists of the α1B-adrenoceptors. Additionally, compounds 10e and 10h were α1A-adrenoceptors antagonist. The dual α1A-/α1B-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0 mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour.

Antiarrhythmic and α-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one.

In an effort to develop α-adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin-2-one derivatives. The α1- and α2-adrenorecepor affinities of the new pyrrolidin-2-one derivatives were determined using a radioligand binding assay. The most active compound was then tested in vitro for intrinsic activity toward α(1A)- and α(1B)-adrenoceptors and in vitro for antiarrhythmic activity in epinephrine-induced arrhythmia in rats. The highest affinity for the α1-adrenoceptor (pK(i) = 7.01) was displayed by 1-{4-[4-(2-methoxy-5-chlorophenyl)-piperazin-1-yl]-methyl}-pyrrolidin-2-one (9). 1-[4-(2-Fluorophenyl)-piperazin-1-yl]-methyl-pyrrolidin-2-one (7) showed the highest affinity toward the α2-adrenoceptor (pK(i) = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both α(1A)- (EC50 = 0.5 nM) and α(1B)- (EC50 = 51.0 nM) adrenoceptors. Compound 9 displayed antiarrhythmic activity in rats (ED50 = 5.0 mg/kg (3.13-7.99)). New derivatives of pyrrolidin-2-one with α1 -adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of α(1A)- and α(1B)-adrenoceptors.

Prazosin-Conjugated Matrices Based on Biodegradable Polymers and α-Amino Acids--Synthesis, Characterization, and in Vitro Release Study.

Novel and promising macromolecular conjugates of the α1-adrenergic blocker prazosin were directly synthesized by covalent incorporation of the drug to matrices composed of biodegradable polymers and α-amino acids for the development of a polymeric implantable drug delivery carrier. The cyto- and genotoxicity of the synthesized matrices were evaluated using a bacterial luminescence test, protozoan assay, and Salmonella typhimurium TA1535. A new urethane bond was formed between the hydroxyl end-groups of the synthesized polymer matrices and an amine group of prazosin, using 1,1'-carbonyldiimidazole (CDI) as a coupling agent. The structure of the polymeric conjugates was characterized by various spectroscopy techniques. A study of hydrogen nuclear magnetic resonance ((1)H-NMR) and differential scanning calorimetry (DSC) thermodiagrams indicated that the presence of prazosin pendant groups in the macromolecule structures increased the polymer's rigidity alongside increasing glass transition temperature. It has been found that the kinetic release of prazosin from the obtained macromolecular conjugates, tested in vitro under different conditions, is strongly dependent on the physicochemical properties of polymeric matrices. Furthermore, the presence of a urethane bond in the macromolecular conjugates allowed for obtaining a relatively controlled release profile of the drug. The obtained results confirm that the pharmacokinetics of prazosin might be improved through the synthesis of polymeric conjugates containing biomedical polymers and α-amino acids in the macromolecule.

Molecular design and synthesis of 1,4-disubstituted piperazines as α(1)-adrenergic receptor blockers.

A new series of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid amide and 3,5,6,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-one derivatives were designed, synthesized, their binding and functional properties as α1-adrenoreceptors blockers were evaluated. A new validated α1-adrenoreceptor blocker pharmacophore model (hypothesis) was generated using Discovery Studio 2.5. The compare-fit study for the designed molecules with the generated hypothesis was fulfilled and several compounds showed significant high fit values. Compounds IVa-c, VIIa-d, VIIIa-c, Xa-c, XIa-d have shown blocking activity ranging from 46.73% up to 94.74% compared to 99.17% for prazosin.

Design, synthesis and alpha1-adrenoreceptor blocking activity of new arylpiperazines containing acetophenone substituents.

Alpha1-AR antagonists are currently first-line therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we report the synthesis of a new series of arylpiperazine derivatives containing acetophenone (3-17) which possess alpha1-adrenoreceptor blocking activity. The in vitro alpha1-adrenoreceptor blocking activity of each derivative was first screened using rabbit thoracic aortic rings by measuring the relaxation response (%) activated by (-)-noradrenaline (3 microM). Compounds 6 and 7 with 2,5-dimethoxy and 2-ethoxy substituent were found to have significant vasodilatory effect. Since the presence of a chiral carbon in the structure, 6 and 7 together with their enantiomers 14-17 were further evaluated by testing diastolic effect on rabbit thoracic aorta, prostate and bladder smooth muscle. The S-enantiomer was found to have more potent diastolic activity than the R-enantiomer and racemate, 17 being the most effective alpha1-adrenoreceptor antagonist. In order to assess tissue selectivity, the antagonistic effect of 17 on the (-)-noradrenaline induced contractile response of isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)) and aorta (alpha(1D)) was characterized finally. Compared with naftopidil (1) and terazosin, compound 17 exhibited higher selectivity (18-fold) for the alpha(1D)-adrenoceptor subtype as compared to the alpha(1B)-adrenoceptor subtype, indicating less cardiovascular side effects for the treatment of LUTS/BPH. These data suggest that the acetophenone is a new effective adrenergic receptor ligand as well as incentivizes further research regarding pharmacological properties of chiral molecules.

Combining on-chip synthesis of a focused combinatorial library with computational target prediction reveals imidazopyridine GPCR ligands.

Using the example of the Ugi three-component reaction we report a fast and efficient microfluidic-assisted entry into the imidazopyridine scaffold, where building block prioritization was coupled to a new computational method for predicting ligand-target associations. We identified an innovative GPCR-modulating combinatorial chemotype featuring ligand-efficient adenosine A1/2B and adrenergic α1A/B receptor antagonists. Our results suggest the tight integration of microfluidics-assisted synthesis with computer-based target prediction as a viable approach to rapidly generate bioactivity-focused combinatorial compound libraries with high success rates.

Discovery of MT-1207: A Novel, Potent Multitarget Inhibitor as a Promising Clinical Candidate for the Treatment of Hypertension.

Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through in vitro and in vivo studies. The most promising compound, II-13 (later named as MT-1207), is a potent α1 and 5-HT2A receptor antagonist with remarkable IC50 in the picomolar level. Importantly, in the in vivo assay, II-13 achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function. Compound II-13, with its significant advantages in terms of pharmacological effects, pharmacokinetic parameters, and a large safety window, was extensively investigated. Moreover, data also showed that compound II-13 had fewer side effects in a postural BP assay and could prevent the onset of postural hypotension. Together, these results suggested that compound II-13 is a highly potent antihypertensive drug candidate with multitarget mechanisms of action in preclinical models. Currently, MT-1207 is in phase II hypertensive clinical trials in China.

Design, synthesis and biological evaluation of novel 7-mercaptocoumarin derivatives as α(1)-adrenoceptor antagonists.

Study on the pharmacophore model of α(1)-adrenoceptor (α(1)-AR) antagonists led to design a series of novel 7-mercaptocoumarin derivatives as α(1)-AR antagonists. All designed compounds have been synthesized and biologically evaluated. The results showed that most of them exhibited strong antagonistic activity. Especially compound 6 showed excellent activity, which was better than that of the reference compound prazosin. Structure-activity relationship studies revealed that small hydrophobic group at the terminal heterocyclic ring and ortho substituents on the phenyl ring of phenylpiperazine moiety were the essential structural factors for α(1)-AR antagonistic activity. The pharmacophore modeling studies further clarified their structural contributions to antagonistic activity and also demonstrated that 7-mercaptocoumarin moiety could be a useful scaffold for design of α(1)-AR antagonists.

Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α1-adrenoceptor antagonistic properties.

The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α(1)-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a-18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro's pharmacophore model and structural properties of previously investigated α(1)-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α(1)-ARs in nanomolar range (40-290 nM). The highest activities (K(i)<75 nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of α(1)-affinities as follows: 3,4-di CH(3)O>2,4-di CH(3)O>4-Cl>2,3-di CH(3)O>H>4-N(CH(3))(2).

Design, synthesis and biological evaluation of new arylpiperazine derivatives bearing a flavone moiety as α1-adrenoceptor antagonists.

Elaborate study on the three-dimensional model of α(1)-adrenoceptor (α(1)-AR) antagonists led to the development of a series of new arylpiperazine derivatives bearing a flavone nucleus as α(1)-AR antagonists. The in vitro activities were evaluated and compounds 1, 4, 10, 13 and 15 showed activities close to the reference compound (Prazosin).

Drug metabolism-based design, synthesis, and bioactivities of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) analogs as α1-adrenoceptors antagonists.

1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) is a potent α1-adrenoceptor antagonist that is currently under Phase II clinic trials. However, the fast metabolism has restricted its further use. In this paper, 11 DDPH analogs were designed according to the probable metabolism pathways of DDPH, and featured the structures of halogen, methyl, and cyano groups at the 3-, or 4-position of aromatic ring A to block the hydroxylation, and one hydroxyl group at the 3-, or 4-position of aromatic ring B to extend the duration time. These compounds were synthesized in moderate to good yields from the reductive amination of substituted phenoxyacetones with substituted phenylethylamines, and fully characterized with ¹H NMR, IR, and HRMS. Biological evaluation indicated that most of the compounds exhibited strong blocking and moderate to good antihypertensive activities. It is clear that the compounds having 4-OH/3-OMe on group B exhibited higher blocking activities and longer duration time than their corresponding analogs having 4-OMe/3-OMe (and also 3-OH/4-OMe). Among them, compound 13 having bromo group at the 4-position of ring A and 4-OH/3-OMe on group B, exhibited the highest blocking activity, whereas compound 17 that had a methyl group at the 4-position of ring A and a hydroxyl group at the 4-position of ring B, was more active than potent DDPH in terms of both blocking and antihypertensive activities. In addition, the possible correlations between the blocking and antihypertensive activities are also briefly discussed.

New aporphinoid 5-HT2A and α1A antagonists via structural manipulations of nantenine.

A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT(2A) and α(1A) receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT(2A) and α(1A) antagonists, respectively. The C2 alkyloxy analogs studied were generally selective for α(1A) versus 5-HT(2A). The C3 bromo analog 15 is one of the most potent aporphinoid 5-HT(2A) antagonists known presently.

Synthesis and blocking activities of isoindolinone- and isobenzofuranone-containing phenoxylalkylamines as potent α(1)-adrenoceptor antagonists.

This paper describes the synthesis and blocking activities of twelve new isoindolinone- and isobenzofuranone-containing phenoxylalkylamines as potent α(1)-Adrenoceptor antagonists. These compounds were synthesized in moderate to good yields starting from 3,4-dimethylphenol, and characterized with (1)H-NMR, MS, IR and elemental analysis. Their blocking activities toward α(1)-Adrenoceptors were evaluated on isolated rat anococcygeus muscles. The results indicated that these compounds were very strong in blocking α(1)-Adrenoceptors, and most of them exhibited activities that were comparable to that of known potent α(1)-Adrenoceptor antagonist 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH).

Rational design, synthesis, biological evaluation, homology and docking studies of coumarin derivatives as α1 -adrenoceptor antagonists.

According to a three-point pharmacophore for some uro-selective α(1) -adrenoceptor (AR) antagonists, a novel class of coumarin (=2H-1-benzopyran-2-one) derivatives have been successfully designed and synthesized with high efficacies for α(1) -AR. These synthesized coumarin derivatives exhibited high efficacies towards α(1) -AR in in vitro pharmacological assays. Compared with prazosin (pK(i) value of 8.77), among those coumarins, tolylpiperazine-substituted derivatives, 7 and 8, have comparable pK(i) values of 8.81 and 8.77, respectively. The trend in efficacies of these coumarin derivatives towards α(1A) -adrenoceptor was further rationalized by intensive molecular docking. Our work demonstrated that the designed coumarin derivatives can inhibit α(1) -AR in vitro. These findings will provide a guide for further studies of the medical therapy of benign prostatic hyperplasia (BPH).

Synthesis, Molecular Modeling of Novel Substituted Pyridazinones and their Vasorelaxant Activities.

BACKGROUND: Hypertension, one of the most common cardiovascular diseases that can cause coronary disease, stroke, myocardial infarction, and sudden death, it is the major contributor to cardiac failure as well as renal insufficiency. OBJECTIVES: As there are many cardio-active pyridazinone-base derivatives in clinical use, therefore, we aimed to synthesize a new series of pyridazin-3-ones and evaluate their vasorelaxant activity. METHODS: A new series of synthesized compounds were carried out first by the synthesis of 6- flouroarylpyridazinones by cyclization of 3-(4-flourobenzoyl) propionic acid with hydrazine hydrate or arylhydrazines to provide the corresponding pyridazinone derivatives 2a-d. Mannich reaction was performed using morpholine or piperidine formaldehyde to obtain compounds 3a,b. On the other hand, reaction of 2a with various chloroacetamide intermediates, in dimethylformamide and potassium carbonate as a catalyst, afforded the target compounds 5a-c. The aromatic acid hydrazide intermediates 6a-g were prepared in 50-90% yield, by reacting to the prepared esters with hydrazine hydrate under reflux in ethanol. The two compounds 8a,b were prepared via condensation of 7a,b with ethyl chloroacetate in dry acetone. Finally, the target 2,4,6-trisubstituted pyridazinones 9a-c derivatives were obtained by the reaction of 7a with the appropriate aromatic aldehyde or substituted acetophenones. The new compounds were then evaluated for their vasorelaxant properties using isolated thoracic rat aortic rings. In addition, a homology model was built and molecular modeling simulation of these compounds into the active sites of the newly created α1a-adrenoceptor model was performed in order to predict and rationalize their affinities toward this receptor. RESULTS: Among these compounds; 5a was the most potent, it exhibited approximately two-times the activity of prazosin (IC50 = 0.250, 0.487 mmol, respectively) also, fourteen compounds were more potent than prazosin.

Structure-activity relationships in 1,4-benzodioxan-related compounds. 10. Novel α1-adrenoreceptor antagonists related to openphendioxan: synthesis, biological evaluation, and α1d computational study.

A series of novel openphendioxan analogues were synthesized and tested at α(1)-adrenoreceptor (AR) subtypes by binding and functional assays. The α(1d)-AR binding profile was also examined by means of 2D, 3D-QSAR together with docking studies. Multiple regression analysis suggested the relevance of adequate number of heteroatoms in the whole molecule and of passive membrane diffusion to enhance α(1d)-AR affinity. Docking simulations against a computational structural model of the biological target further proved this evidence and furnished support for chemiometric analysis, where polar, electrostatic, hydrophobic and shape effects of the ortho substituents in the phenoxy terminal, most likely governing ligand binding, helped the depiction of pharmacophore hypothesis for the examined ligands data set.