RESUMEN

Bilastine (BIL) is a novel 2nd generation antihistamine medication is used to treat symptoms of chronic urticaria and allergic rhinitis. However, its poor solubility limits its therapeutic efficacy. In order to enhance the physicochemical characteristics of BIL, various molecular adducts of BIL (Salt, hydrate and co-crystal) were discovered in this study using two distinct salt-formers: Terephthalic acid (TA), 2,4-Dihydroxybenzoic acid (2,4-DHBA), and three nutraceuticals (Vanillic Acid (VA), Hydroquinone (HQN) and Hippuric acid (HA)). Various analytical methods were used to examine the synthesised adducts, including Powder X-Ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SCXRD), and thermal analysis (Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC)). Single-crystal X-ray diffraction (SCXRD) studies avowed that the architectures of the molecular adducts are maintained in the solid state by an array of strong (N+H⋯O-, NH⋯O, OH⋯O) and weak (CH⋯O) hydrogen bonds. Additionally, a solubility test was performed to establish the in vitro release characteristics of newly synthesised BIL adducts and it observed that most of the molecular adducts exhibit higher rates of dissolution in comparison to pure BIL; in particular, BIL.TA.HYD showed the highest solubility and the fastest rate of dissolution. Moreover, experiments on flux permeability and diffusion demonstrated that the BIL.TA.HYD and BIL.VA salts had strong permeability and a high diffusion rate. In addition, the synthesized adduct's stability was assessed at 25 °C and 90 % ± 5 % relative humidity, and it was found that all the molecular salts were stable and did not undergo any phase changes or dissociation. The foregoing result leads us to believe that the newly synthesized molecular adducts' increased permeability and solubility will be advantageous for the creation of novel BIL formulations.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1 , Cristalografía por Rayos X , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Modelos Moleculares , Estructura Molecular , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacología , Ácidos Ftálicos/síntesis química , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Solubilidad

RESUMEN

INTRODUCTION: Histamine, a biological amine, is considered as a principal mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. Numerous derivatives have been developed that strive with histamine at the H1 receptor and prevent binding of histamine at the H1 receptor, thereby preventing allergic reactions. Molecules containing a triazole ring fused with six-membered ring systems are found to possess broad applications in the field of medicine and industry. The present study is an attempt to characterize the impact of the nature of the substituent introduced at 5 positions of the-4H-1,2,4-triazole-3-thiol on their capacities to bind with the H1 receptor. METHODS: Molecular docking (PDB ID: 3RZE) revealed that synthesized derivatives and target proteins were actively involved in binding with Tyr-108, Thr-112, Ala-216, and Phe-432 subunits. A pharmacophore model, new 5-(4-substituted phenyl)-4-(phenylamino)-4-H-1,2,4-triazole-3- thiols (5a-5h) were designed and evaluated for H1-blocking activity using isolated segments from the guinea pig ileum. RESULTS: According to in silico analysis, all the compounds have a topological polar surface area (TPSA) less than 140 Å squared, so they tend to easily penetrate cell membranes. The results show that most of the compounds are non-inhibitors of CYP450 substrates that play a fundamental role in drug metabolism. Compounds 5d (50.53±12.03), 5h (50.62±12.33) and 7a (55.07±12.41) are more active than others. CONCLUSION: Finally, these derivatives were screened for H1 receptor antagonist activity using guinea pig ileum, taking chlorpheniramine maleate as a standard. Most of the compounds were found to possess better antihistamine activity.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1/farmacocinética , Receptores Histamínicos H1/metabolismo , Triazoles/farmacocinética , Animales , Clorfeniramina/administración & dosificación , Clorfeniramina/farmacocinética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Absorción Gastrointestinal , Cobayas , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/síntesis química , Simulación del Acoplamiento Molecular , Triazoles/administración & dosificación , Triazoles/síntesis química

RESUMEN

In this study, a series of novel ethylenediamine compounds were obtained by structural modification of the lead compounds with thonzylamine, and using the principle of modifying by bioisostere formation and modification with alkyl groups. In vitro assay, the biological activities showed that the target compounds have good properties in inhibiting mast cell degranulation and releasing histamine and ß-aminohexidase, such as the compounds 5c, 5g, 5k, 5l and 5o, especially of compound 5k to mast cell degranulation is IC50 = 0.0106 ±â€¯0.001 µmol⋅L-1, histamine release was IC50 = 0.0192 ±â€¯0.005 µmol⋅L-1 and ß-hexosaminidase release was IC50 = 0.0455 ±â€¯0.002 µmol⋅L-1in vitro. At the same time, in vivo biological activities assay results showed that have a good Histamie induce bronchospasm effect with relatively long duration and good protective effect in vivo, among which the protective effect of compound 5k was 79.74 ±â€¯0.30%, compounds 5c, 5g, 5k, 5l and 5o could inhibit the capillary permeability of increasing which were caused by histamine.

Asunto(s)

Diseño de Fármacos , Etilenodiaminas/química , Etilenodiaminas/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Animales , Basófilos/efectos de los fármacos , Basófilos/metabolismo , Línea Celular , Clorfeniramina , Etilenodiaminas/síntesis química , Femenino , Cobayas , Antagonistas de los Receptores Histamínicos H1/síntesis química , Humanos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Distribución Aleatoria , Ratas , Receptores Histamínicos H1/química , Receptores Histamínicos H1/metabolismo

RESUMEN

A practical and sustainable method for the synthesis of levocabastine hydrochloride (1), a H1 receptor antagonist for the treatment of allergic conjunctivitis, that can be applied to the industrial production of the compound has been developed. Substantial improvements over the previously reported procedure are achieved via efficient preparation of an optically active key intermediate (5) without chiral resolution and with a more effective detosylation, which complements the previous procedure. Notably, our process requires no chromatographic purification and provides levocabastine hydrochloride in greater than 99.5% purity in a 14.2% overall yield.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1/síntesis química , Piperidinas/síntesis química , Antagonistas de los Receptores Histamínicos H1/química , Estructura Molecular , Piperidinas/química

RESUMEN

A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.

Asunto(s)

Descubrimiento de Drogas , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacología , Quinolinas/farmacología , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/metabolismo , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/química , Humanos , Ligandos , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad

RESUMEN

The first asymmetric synthesis of (R,R)-clemastine (1) has been accomplished by the coupling of (R)-tertiary alcohol 2 and (R)-chloroethylpyrrolidine 3 via O-alkylation. (R)-Tertiary alcohol 2 was synthesized by stereoselective alkylation of chiral α-benzyloxy ketone with Grignard reagent via chelation-controlled 1,4-asymmetric induction. In the reaction, chiral benzyl group acts as a chiral auxiliary as well as a protecting group. (R)-Chloroethylpyrrolidine 3 was prepared by asymmetric transformation starting with L-homoserine lactone, in which racemization-minimized N-allylation and ring-closing metathesis were involved as key steps.

Asunto(s)

Química Farmacéutica/métodos , Clemastina/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Receptores Histamínicos H1/química , Estereoisomerismo

RESUMEN

In this study, we have synthesized and elucidated the structure of the H1 histamine antagonist, 2-(1-methylpiperidin-4-ylidene)-4,7-diazatricyclo[8.4.0.0((3,7))]tetradeca-1(14),3,5,10,12-pentaene-6-carbaldehyde in the solution and solid-state. We have also studied the thermal dilapidation of the compound. Solution structure analysis was achieved by employing NMR spectroscopy including 2D experiments NOESY, HSQC and HMBC, while solid state investigations were undertaken using SXRD, PXRD, TGA, DSC, and IR spectroscopy. For the first time the single crystal structure of alcaftadine has now been solved. Crystallographic data are as follows: monoclinic, Cc, a=11.5694(6)Å, b=14.5864(6)Å, c=10.2688(4)Å, α=90°, ß=111.793(3)°, γ=90°, V=1609.07(13)Å(3), Z=4. The Hirshfeld surface analyses also have been performed using the crystal structure.

Asunto(s)

Benzazepinas/química , Antagonistas de los Receptores Histamínicos H1/química , Imidazoles/química , Benzazepinas/síntesis química , Rastreo Diferencial de Calorimetría , Cristalografía por Rayos X , Antagonistas de los Receptores Histamínicos H1/síntesis química , Imidazoles/síntesis química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Termogravimetría

RESUMEN

As a part of a research project pertaining to the synthesis of novel candidates as nonsedating, nonclassic H1 histaminergic (H1) blockers with low toxicity profiles, some new 5-substituted aminomethylenepyrimidine-2,4,6-triones were designed based on the H1 histaminic receptor pharmacophore model. The interactions between the designed compounds and the H1 receptor were studied using molecular docking on the homology model of H1 receptor. The designed compounds were synthesized and biologically evaluated for H1-blocking activity; using isolated segments of guinea pig ileum. Compounds 15,18,19 and 21 exhibited comparable activities to acrivastine (22) as reference nonsedating drug. The C log P of designed compounds revealed lower values in reference to acrivastine (22) which might indicate decreased tendency for crossing the blood brain barrier.

Asunto(s)

Diseño Asistido por Computadora , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Animales , Cobayas , Antagonistas de los Receptores Histamínicos H1/química , Masculino , Modelos Químicos , Unión Proteica/efectos de los fármacos , Pirimidinonas/química , Relación Estructura-Actividad

RESUMEN

Astemizole, a H1R antagonist shows high affinity to the histamine H1 receptor but only a moderate affinity to the histamine H4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H1 receptor and to increase affinity to the histamine H4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H1 and H4 receptors. The new compounds show affinity to the histamine H1 receptor in the pK i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H4 receptor was surprisingly rather low (pK i from 4.4 to 5.6). Three representative compounds were docked into the histamine H1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H4 receptor, a H1/H4-pharmacophore hypothesis was developed.

Asunto(s)

Astemizol/farmacología , Indoles/farmacología , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos/efectos de los fármacos , Animales , Astemizol/síntesis química , Astemizol/química , Femenino , Cobayas , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Indoles/síntesis química , Indoles/química , Masculino , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piperazinas/síntesis química , Piperazinas/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H4 , Células Sf9 , Spodoptera

RESUMEN

Premedication with a combination of histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H2R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H1R) and the isolated spontaneously beating right atrium (H2R) of the guinea pig. The results indicate that, depending on the nature of the H2R antagonist partial structure, the highest H1R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H1R, ileum) and 7.73 (H2R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H1R) and 6.61 (H2R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties.

Asunto(s)

Guanidinas/química , Guanidinas/síntesis química , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores H2 de la Histamina/química , Animales , Cimetidina/análogos & derivados , Cimetidina/química , Cobayas , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores H2 de la Histamina/síntesis química , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Piperidinas/química , Pirilamina/química

RESUMEN

A series of N-substituted desloratadine analogues were designed and synthesized. They were tested for H1 antihistamine activity by inhibiting histamine-induced contraction of isolated ileum muscles of guinea-pigs in vitro and inhibiting histamine-induced asthmatic reaction in guinea-pigs in vivo. All the evaluated compounds exhibited significant antihistamine activity compared with desloratadine. Five active compounds induced no sedative effects on mouse and four of them exhibited lower anticholinergic side effects than desloratadine. Among these analogues, compound 10, (1S,4S)-4-chlorocyclohexyl desloratadine displayed the highest activity and best safety profile. And it was believed to be a potential candidate as the 3rd generation antihistamine.

Asunto(s)

Diseño de Fármacos , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Loratadina/análogos & derivados , Animales , Estabilidad de Medicamentos , Células HEK293 , Antagonistas de los Receptores Histamínicos H1/química , Humanos , Concentración de Iones de Hidrógeno , Loratadina/síntesis química , Loratadina/química , Loratadina/farmacología , Ratones , Unión Proteica/efectos de los fármacos

RESUMEN

A series of novel 2-(3-substituted propyl)-3-(2-methyl phenyl) quinazolin-4-(3H)-ones were synthesized by the reaction of 2-(3-bromopropyl thio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one with various amines. The starting material, 2-(3-bromopropyl thio)-3-(2-methyl phenyl) quinazolin-4-(3H)-one was synthesized from 2-methyl aniline. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. Compound 2-(3-(4-methylpiperazin-1-yl) propylthio)-3-(2-methyl phenyl) quinazolin-4(3H)-one (OT5) emerged as the most active compound (71.70% protection) of the series when compared to the reference standard chlorpheniramine maleate (70.09% protection). Compound OT5 shows negligible sedation (7%) compared to chlorpheniramine maleate (33%). Therefore, compound OT5 can serve as the leading molecule for further development into a new class of H(1)-antihistaminic agents.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Quinazolinas/química , Animales , Espasmo Bronquial/prevención & control , Técnicas de Química Sintética , Clorfeniramina/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Cobayas , Antagonistas de los Receptores Histamínicos H1/química , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Piperazinas/farmacología , Quinazolinonas/farmacología , Relación Estructura-Actividad

RESUMEN

5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a ß-ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H(1) receptor antagonists. All four mono-azaphthalazinone series had higher affinity (pK(i)) for the human H(1) receptor than azelastine, but were not as potent as the parent non-aza phthalazinone. The 5,8-diazaphthalazinone was equipotent with azelastine. The least potent series were the 7-azaphthalazinones, whereas the 5-azaphthalazinones were the most lipophilic. The more hydrophilic series were the 8-aza series. Replacement of the N-methyl substituent on the pyrrolidine with the n-butyl group caused an increase in potency (pA(2)) and a corresponding increase in lipophilicity. Introduction of a ß-ether oxygen in the n-butyl analogues (2-methoxyethyl group) decreased the H(1) pA(2) slightly, and increased the selectivity against hERG. The duration of action in vitro was longer in the 6-azaphthalazinone series. The more potent and selective 6-azaphthalazinone core was used to append an H(3) receptor antagonist fragment, and to convert the series into the long acting single-ligand, dual H(1) H(3) receptor antagonist 44. The pharmacological profile of 44 was very similar to our intranasal clinical candidate 1.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1/síntesis química , Ftalazinas/química , Piridazinas/síntesis química , Piridinas/síntesis química , Receptores Histamínicos H1/química , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Canales de Potasio Éter-A-Go-Go/metabolismo , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Ftalazinas/síntesis química , Ftalazinas/farmacología , Unión Proteica/efectos de los fármacos , Pirazinas/química , Piridazinas/química , Piridazinas/farmacología , Piridinas/química , Piridinas/farmacología , Receptores Histamínicos H1/metabolismo , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

A series of novel 3-(4-chlorophenyl)-2-(3-substituted propyl) quinazolin-4-(3H)-ones have been synthesized and tested for their in vivo H1-antihistaminic activity on conscious guinea pigs. All the test compounds have protected the animals from histamine induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(3-(4-methylpiperazin-1-yl) propylthio) quinazolin-4(3H)-one (PC5) emerged as the most active compound (77.53% protection) of the series when compared to the reference standard chlorpheniramine maleate (70.09% protection). Compound PC5 shows negligible sedation (6.16%) compared to chlorpheniramine maleate (29.58%). Therefore, compound PC5 can serve as the lead molecule for further development into a new class of H1-antihistaminic agents.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Animales , Espasmo Bronquial/inducido químicamente , Espasmo Bronquial/prevención & control , Clorfeniramina/farmacología , Cobayas , Histamina/administración & dosificación , Masculino

RESUMEN

In addition to their antihistamine effects, H1-receptor antagonists possess pharmacological properties that are not uniformly distributed among this class of drugs, such as anti-inflammatory, anti-allergic and antiplatelet activities. In this paper, Cyclizine (1-benzhydryl-4-methyl-piperazine, I), bromodiphenhydramine (2-[(4-bromophenyl)-phenylmethoxy]-N, N-dimethylethanamine, II) and some of their new piperazine and ethanolamine derivatives (III-VIII) inducing changes in substitution of phenyl and amine moieties were synthesized and their acute and chronic antiinflammatory effects were evaluated by standard pharmacological tests. The results showed that substitution of phenyl by tolyl, anisol and cumene groups in piperazine family could remarkably decrease acute inflammation in these new drugs. Also, substitution of dimethylamine by morpholine group could not decrease this inflammation in new synthesized ethanolamine family. But the results from the cotton pellet-induced granuloma formation in rats showed that none of drugs (I-VIII) were effective to reduce the chronic inflammation.

Asunto(s)

Antiinflamatorios/química , Etanolamina/química , Antagonistas de los Receptores Histamínicos H1/química , Piperazinas/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/uso terapéutico , Fibra de Algodón , Difenhidramina/análogos & derivados , Difenhidramina/síntesis química , Difenhidramina/química , Difenhidramina/uso terapéutico , Edema/inducido químicamente , Edema/tratamiento farmacológico , Etanolamina/síntesis química , Etanolamina/uso terapéutico , Granuloma/inducido químicamente , Granuloma/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Masculino , Piperazina , Piperazinas/síntesis química , Piperazinas/uso terapéutico , Ratas , Ratas Wistar , Receptores Histamínicos H1/química , Receptores Histamínicos H1/metabolismo

RESUMEN

A structure-activity relationship (QSAR) analysis of 19 thiazole derivatives with H1-antihistamine activity was carried out. The semi-empirical method AMI was employed to calculate a set of physicochemical parameters for investigated compounds. The principal component analysis (PCA), discriminant function analysis (DFA) and regression analysis (RA) were employed to reduce dimensionality and investigate which subset of variables is effective for classifying the thiazole derivatives according to their degree of anti-H1 activity. In PCA the studied compounds were separated into two groups: group A with lower degree of H,-antihistamine activity and group B with higher activity. The DFA showed that the parameters: alpha (polarizability), AB (distance between aliphatic and aromatic nitrogen atoms), Eb (binding energy), Hh (hydration energy), eHOMO (HOMO energy), and QAr are responsible for separation between compounds exhibiting higher and lower H1-antihistamine activity. The importance of hydrophobic and steric parameters for thiazole derivatives 1-19 with HL-antihistamine activity was established via RA. On the basis of PCA, DFA and RA methods, a prediction rule for classifying new thiazole derivatives with H1-antihistamine activity was elaborated.

Asunto(s)

Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Análisis Discriminante , Diseño de Fármacos , Conformación Molecular , Análisis de Componente Principal , Relación Estructura-Actividad Cuantitativa , Análisis de Regresión , Relación Estructura-Actividad

RESUMEN

A series of tricyclic carboxylic acids having 6-amino-pyrimidine-2,4(1H,3H)-dione with piperazino or homopiperazino moiety linked by propylene, were synthesized and evaluated for their affinity toward human histamine H(1) receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice, bioavailability in rats, and their anti-inflammatory activity in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, dibenzoxazepine carboxylic acid 13b showed both histamine H(1) receptor antagonistic activity and anti-inflammatory activity in vivo. In addition, 13b exhibited low affinity toward α(1) receptor and low occupancy of H(1) receptor in the brain. It is therefore, believed that 13b is a potential candidate for development as 3rd generation anti-histamine.

Asunto(s)

Antiinflamatorios/química , Ácidos Carboxílicos/química , Antagonistas de los Receptores Histamínicos H1/química , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Azepinas/síntesis química , Azepinas/química , Azepinas/farmacología , Células CACO-2 , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Permeabilidad de la Membrana Celular , Ciclización , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Ratones , Oxazepinas/síntesis química , Oxazepinas/química , Oxazepinas/farmacología , Unión Proteica , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Receptores Histamínicos H1/química , Receptores Histamínicos H1/metabolismo , Relación Estructura-Actividad

RESUMEN

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a ß-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.

Asunto(s)

Citocromo P-450 CYP2D6/química , Antagonistas de los Receptores Histamínicos H1/química , Indenos/química , Pirazinas/química , Receptores Histamínicos H1/química , Biotransformación , Citocromo P-450 CYP2D6/metabolismo , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Indenos/síntesis química , Indenos/farmacocinética , Pirazinas/síntesis química , Pirazinas/farmacocinética , Receptores Histamínicos H1/metabolismo , Relación Estructura-Actividad

RESUMEN

Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.

Asunto(s)

Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Hipnóticos y Sedantes/síntesis química , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Sueño/efectos de los fármacos , Compuestos de Espiro/síntesis química , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.

Asunto(s)

Bencimidazoles/química , Sistema Nervioso Central/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H1/química , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Bencimidazoles/síntesis química , Bencimidazoles/uso terapéutico , Descubrimiento de Drogas , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Relación Estructura-Actividad