RESUMO
Bilastine (BLA), 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2-yl)-piperidin-1-yl)-ethyl)-phenyl)-2-methylpropanoic acid, is an active antihistamine drug. With the idea of repurposing drugs from the existing pool of 'active' pharmaceutical ingredients, the therapeutic potency of bilastine as an anticancer agent was investigated via the tailored synthesis of a metal-based anticancer drug formulation of the type [BLA(phen)2M(II)]+·X-, where M = Co, Cu, and Zn and X- = NO3 and ClO4. The synthesized metal-based chemotherapeutics derived from the bilastine drug that acts as a ligand were thoroughly characterized using spectroscopic techniques, namely, UV-vis, FT-IR, and EPR (in the case of 1 and 2); 1H-NMR and 13C-NMR (in the case of 3); ESI-MS and single-crystal X-ray diffraction studies. Comprehensive biological studies (DNA binding, cleavage, and cytotoxic activity) using various biophysical and gel electrophoretic methods were carried out to validate their potential as anticancer agents. The cytotoxic activity of 'therapeutically promising' copper(II)-based drug candidate 2 was evaluated against MCF-7, MBA-MD-231, HeLa, HepG2, and Mia-PaCa-2 cancer cells via an SRB assay, and the results demonstrated 2 as a potent anticancer agent at low nanomolar concentrations against all tested cancer cells, preferably with a much superior anticancer efficacy against human pancreatic cancer cells.
Assuntos
Antineoplásicos , Cobalto , Complexos de Coordenação , Cobre , Reposicionamento de Medicamentos , Zinco , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Cobre/química , Cobre/farmacologia , Zinco/química , Zinco/farmacologia , Cristalografia por Raios X , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Cobalto/química , Cobalto/farmacologia , Modelos Moleculares , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese químicaRESUMO
The use of histamine H3 receptor (H3 R) antagonists is becoming a promising therapeutic approach for epilepsy. In this paper, a series of novel nonimidazole H3 R antagonists was synthesized and screened as antiepileptic drugs. All of these prepared antagonists displayed micromolar or submicromolar H3 R antagonistic activities in the cAMP response element luciferase screening assay. Compounds 5a (IC50 = 0.11 µM), 5b (IC50 = 0.56 µM), and 5f (IC50 = 0.78 µM) displayed the most potent H3 R antagonistic activities, with considerable potency when compared with pitolisant (IC50 = 0.51 µM). In the maximal electroshock (MES)-induced seizure model, compounds 5c, 5e, and 5g showed obvious protection for the electrostimulated mice, and the protection of 5g against the MES-induced seizures was fully abrogated when mice were cotreated with R-(α)-methyl-histamine, a central nervous system-penetrant H3 R agonist, suggesting that the potential therapeutic effect of 5g was observed to work through H3 R. These results indicate that the attempt to find a new antiepileptic drug among H3 R antagonists is practicable, but it is necessary to consider the log P of the molecules to ensure penetration of the blood-brain barrier.
Assuntos
Anticonvulsivantes/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Oxazóis/farmacologia , Receptores Histamínicos H3/metabolismo , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Endogâmicos , Simulação de Acoplamento Molecular , Estrutura Molecular , N-Metilaspartato , Oxazóis/química , Convulsões/induzido quimicamente , Convulsões/metabolismo , Relação Estrutura-AtividadeRESUMO
Histamine acts through four different receptors (H1R-H4R), the H3R and H4R being the most explored in the last years as drug targets. The H3R is a potential target to treat narcolepsy, Parkinson's disease, epilepsy, schizophrenia and several other CNS-related conditions, while H4R blockade leads to anti-inflammatory and immunomodulatory effects. Our group has been exploring the dihydrobenzofuranyl-piperazines (LINS01 series) as human H3R/H4R ligands as potential drug candidates. In the present study, a set of 12 compounds were synthesized from adequate (dihydro)benzofuran synthons through simple reactions with corresponding piperazines, giving moderate to high yields. Four compounds (1b, 1f, 1g and 1h) showed high hH3R affinity (pKi > 7), compound 1h being the most potent (pKi 8.4), and compound 1f showed the best efficiency (pKi 8.2, LE 0.53, LLE 5.85). BRET-based assays monitoring Gαi activity indicated that the compounds are potent antagonists. Only one compound (2c, pKi 7.1) presented high affinity for hH4R. In contrast to what was observed for hH3R, it showed partial agonist activity. Docking experiments indicated that bulky substituents occupy a hydrophobic pocket in hH3R, while the N-allyl group forms favorable interactions with hydrophobic residues in the TM2, 3 and 7, increasing the selectivity towards hH3R. Additionally, the importance of the indole NH in the interaction with Glu5.46 from hH4R was confirmed by the modeling results, explaining the affinity and agonistic activity of compound 2c. The data reported in this work represent important findings for the rational design of future compounds for hH3R and hH4R.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Piperazinas/farmacologia , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H4/antagonistas & inibidores , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Receptores Histamínicos H4/metabolismo , Relação Estrutura-AtividadeRESUMO
Analogues of the conformationally dynamic Claritin (loratadine) and Clarinex (desloratadine) scaffolds have been enantio- and chemoselectively N-oxidized using an aspartic acid containing peptide catalyst to afford stable, helically chiral products in up to >99:1 er. The conformational dynamics and enantiomeric stability of the N-oxide products have been investigated experimentally and computationally with the aid of crystallographic data. Furthermore, biological assays show that rigidifying the core structure of loratadine and related analogues through N-oxidation affects antihistamine activity in an enantiomer-dependent fashion. Computational docking studies illustrate the observed activity differences.
Assuntos
Ácido Aspártico/química , Antagonistas dos Receptores Histamínicos/farmacologia , Loratadina/farmacologia , Peptídeos/química , Receptores Histamínicos/metabolismo , Catálise , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Humanos , Loratadina/análogos & derivados , Loratadina/química , Conformação Molecular , Simulação de Acoplamento Molecular , EstereoisomerismoRESUMO
Novel reactions using hetero-heavy atoms (P, S, Si, Se, and Sn) were developed and applied to the synthesis of biofunctional molecules and some medicine-candidates, in which the following items are covered. 1) Development of introduction of C1-unit using cyanophosphates (CPs). 2) Carbene-generation under neutral condition from CPs and its application to organic synthesis. 3) [3,3]Sigmatropic rearrangement-ring expansion reactions of medium-sized cyclic thionocarbonates containing a sulfur atom and their application to natural product synthesis. 4) Stereoselective synthesis of novel ß-imidazole C-nucleosides via diazafulvene intermediates and their application to investigating ribozyme reaction mechanism. 5) Developments of novel histamine H3- and H4-receptor ligands using new synthetic methods involving Se or Sn atoms.
Assuntos
Produtos Biológicos/química , Metais/química , Animais , Produtos Biológicos/síntese química , Proliferação de Células/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Metano/análogos & derivados , Metano/química , Metano/metabolismo , Nitrilas/química , Nucleosídeos/síntese química , Nucleosídeos/químicaRESUMO
Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H3R was validated with washout experiments and leads to inverse agonism on H3R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H3R conformation and to study the consequences of prolonged inhibition of the H3R.
Assuntos
Isotiocianatos/síntese química , Receptores Histamínicos H3/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Agonismo Inverso de Drogas , Células HEK293 , Agonistas dos Receptores Histamínicos/síntese química , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Isotiocianatos/química , Isotiocianatos/farmacologia , Ligantes , Receptores Histamínicos H3/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H3 and H4 receptor subtypes. In this study, to develop H4 selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H4 selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H3 and H4 receptors comparable to that of a well-known non-selective H3/H4 antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H3/H4 ligands in the H4 receptor can be different from those of the indole/benzimidazole-piperazine derivatives.
Assuntos
Ciclopropanos/química , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos/síntese química , Ligantes , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H4/metabolismo , Benzimidazóis/química , Benzimidazóis/metabolismo , Ciclopropanos/metabolismo , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/metabolismo , Humanos , Imidazóis/química , Imidazóis/metabolismo , Indóis/química , Indóis/metabolismo , Ligação Proteica , Receptores Histamínicos H3/química , Receptores Histamínicos H4/química , Relação Estrutura-AtividadeRESUMO
The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been developed yet. Here, we have discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets. A pharmacophore-based virtual screening system constructed in-house successfully identified initial hit compound 9, and the subsequent homology model-guided optimization efficiently led us to discover pyrido[2,3- e]tetrazolo[1,5- a]pyrazine analogue 48 as a novel chemotype of a potent and highly selective H4R antagonist. Importantly, orally administered compound 48 exhibits remarkable efficacy on antipruritus and anti-inflammation with a favorable pharmacokinetic (PK) profile in several mouse models of AD. Thus, these data strongly suggest that our compound 48 is a promising clinical candidate for treatment of AD.
Assuntos
Dermatite Atópica/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/uso terapêutico , Receptores Histamínicos H4/antagonistas & inibidores , Animais , Disponibilidade Biológica , Simulação por Computador , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Feminino , Antagonistas dos Receptores Histamínicos/farmacocinética , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Prurido/tratamento farmacológico , Receptores Histamínicos H4/metabolismo , Relação Estrutura-AtividadeRESUMO
H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS-531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior.
Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/síntese química , Piperazinas/síntese química , Receptores Histamínicos H3/metabolismo , Tiazóis/síntese química , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Química Encefálica/fisiologia , Dopamina/metabolismo , Comportamento Alimentar/fisiologia , Cobaias , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Injeções Subcutâneas , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Ligantes , Masculino , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/metabolismo , Permeabilidade , Piperazinas/farmacologia , Ratos , Proteínas Recombinantes/metabolismo , Serotonina/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacologiaRESUMO
Gallic acid (3,4,5-trihydroxybenzoic acid), is a natural product found in various foods and herbs that are well known as powerful antioxidants. Our previous report demonstrated that it inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. In this report, various amide analogs of gallic acid have been synthesized by introducing different amines through carbodiimide-mediated amide coupling and Pd/C-catalyzed hydrogenation. These compounds showed a modest to high inhibitory effect on histamine release and pro-inflammatory cytokine expression. Among them, the amide bearing (S)-phenylglycine methyl ester 3d was found to be more active than natural gallic acid. Further optimization yielded several (S)- and (R)-phenylglycine analogs that inhibited histamine release in vitro. Our findings suggest that some gallamides could be used as a treatment for allergic inflammatory diseases.
Assuntos
Ácido Gálico/análogos & derivados , Ácido Gálico/química , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/uso terapêutico , Inflamação/tratamento farmacológico , Mastócitos/imunologia , Animais , Antagonistas dos Receptores Histamínicos/química , Humanos , Hipersensibilidade/tratamento farmacológicoRESUMO
Synthesis and biological evaluation of a new class of histamine H4 receptor ligands, distinct from the previously reported chemotypes, are described. A virtual screening of our corporate compound collection identified a hit with an undesired dual H3R/H4R activity. Chemical exploration led to the discovery of a more potent and selective 2-benzothiazolylphenylmethyl ether lead compound.
Assuntos
Benzotiazóis/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Benzotiazóis/química , Benzotiazóis/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Receptores Histamínicos , Receptores Histamínicos H4RESUMO
Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90â min with a productivity of 2â mmol h(-1) .
Assuntos
Álcoois/química , Técnicas de Química Sintética/métodos , Cinarizina/síntese química , Ciclizina/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Piperazinas/síntese química , Compostos de Benzil/química , Cinarizina/química , Ciclizina/química , Antagonistas dos Receptores Histamínicos/química , Estrutura Molecular , Piperazinas/químicaRESUMO
A series of novel 1-phenyl-3-hydroxy-4-pyridinone derivatives were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy through incorporation of 3-hydroxy-4-pyridinone moiety from deferiprone into the scaffold of H3 receptor antagonists. Most of these new compounds displayed designed quadruple functions, H3 receptor antagonism, Aß aggregation inhibition, metal ion chelation, and radical scavenging. Especially, the most promising compound 5c displayed nanomolar IC50 values in H3 receptor antagonism with high selectivity, efficient capability to interrupt the formation of Aß(1-42) fibrils, good copper and iron chelating properties, and more potent 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS(â¢+)) scavenging activity than Trolox. Further biological evaluation revealed that it did not show obvious cytotoxicity and hERG potassium channel inhibition at micromolar concentration. In addition, compound 5c demonstrated suitable pharmacokinetic properties and acceptable blood-brain barrier (BBB) permeability in vivo. All these results indicate that compound 5c is a potential multifunctional candidate for AD therapy.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/química , Antipsicóticos/uso terapêutico , Piridonas/química , Piridonas/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Antipsicóticos/síntese química , Antipsicóticos/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Quelantes/química , Quelantes/uso terapêutico , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Agregação Patológica de Proteínas/tratamento farmacológico , Piridonas/farmacocinéticaAssuntos
Anticoncepcionais Orais Hormonais/história , Áustria , Anticoncepcionais Orais Hormonais/síntese química , Cortisona/síntese química , Drama/história , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/história , História do Século XX , História do Século XXI , Literatura Moderna/história , Noretindrona/síntese química , Noretindrona/história , Estados UnidosRESUMO
An efficient C-C bond formation strategy between aromatic/heteroaromatic π-nucleophiles and Lewis acid activated aldehydes is described. This aromatic electrophilic substitution reaction of arenes or heteroarenes is facilitated by Lewis acid AlBr3. Aromatic rings with electron donating substituents are excellent nucleophilic counterparts in this reaction, generating carbinols in excellent yields (61-94%). The formation of triarylmethanes is also witnessed in the case of certain reactive aldehydes and aromatic π-nucleophiles through reactive carbocation formation. The formation of triarylmethane is reduced to a greater extent via retardation of the second π-nucleophile addition through a Lewis base, for example, pyridine, coordination with an aluminium alkoxide intermediate. Various aliphatic aldehydes also underwent Friedel-Crafts type hydroxyalkylation and generated the expected carbinols in moderate yields (41-53%) in the presence of AlBr3. This protocol has been successfully applied to the synthesize of the (±)-carbinoxamine, a therapeutically important histamine H1 antagonist, in a one-pot manner.
Assuntos
Ácidos de Lewis/química , Piridinas/síntese química , Alquilação , Anisóis/química , Benzaldeídos/química , Catálise , Elétrons , Éter/química , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Hidroxilação , Piridinas/químicaRESUMO
Melatonin is an endogenous molecule involved in many pathophysiological processes. In addition to the control of circadian rhythms, its antioxidant and neuroprotective properties have been widely described. Thus far, different bivalent compounds composed by a melatonin molecule linked to another neuroprotective agent were synthesized and tested for their ability to block neurodegenerative processes in vitro and in vivo. To identify a novel class of potential neuroprotective compounds, we prepared a series of bivalent ligands, in which a prototypic melatonergic ligand is connected to an imidazole-based H3 receptor antagonist through a flexible linker. Four imidazolyl-alkyloxy-anilinoethylamide derivatives, characterized by linkers of different length, were synthesized and their binding affinity for human MT1, MT2 and H3 receptor subtypes was evaluated. Among the tested compounds, 14c and 14d, bearing a pentyl and a hexyl linker, respectively, were able to bind to all receptor subtypes at micromolar concentrations and represent the first bivalent melatonergic/histaminergic ligands reported so far. These preliminary results, based on binding affinity evaluation, pave the way for the future development of new dual-acting compounds targeting both melatonin and histamine receptors, which could represent promising therapeutic agents for the treatment of neurodegenerative pathologies.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Receptor MT1 de Melatonina/antagonistas & inibidores , Receptor MT2 de Melatonina/antagonistas & inibidores , Receptores Histamínicos H3/química , Sítios de Ligação , Antagonistas dos Receptores Histamínicos/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Ligantes , Simulação de Acoplamento Molecular , Piperidinas/síntese química , Piperidinas/química , Ligação Proteica , Estrutura Terciária de Proteína , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptores Histamínicos H3/metabolismoRESUMO
The synthesis and the identification of histamine marked a milestone in both pharmacological and immunological research. Since Sir Henry Dale and Patrick Laidlaw described some of its physiological effects in vivo in 1910, histamine has been shown to play a key role in the control of gastric acid secretion and in allergic disorders. Using selective agonists and antagonists, as well as molecular biology tools, four histamine receptors (H1R, H2R, H3R and H4R) have been identified. The Nobel Prize in Physiology and Medicine was awarded to Daniel Bovet in 1957 for the discovery of antihistamines (anti-H1R) and to Sir James Black in 1988 for the identification of anti-H2R antagonists. Anti-H1R and anti-H2R histamine receptor antagonists have revolutionized the treatment of certain allergic disorders and gastric acid-related conditions, respectively. More recently, anti-H3R antagonists have entered early-phase clinical trials for possible application in obesity and a variety of neurologic disorders. The preferential expression of H4R by several immune cells and its involvement in the development of allergic inflammation provide the rationale for the use of anti-H4R antagonists in allergic and in other immune-related disorders.
Assuntos
Antagonistas dos Receptores Histamínicos/metabolismo , Receptores Histamínicos/metabolismo , Animais , Encéfalo/metabolismo , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Hipersensibilidade/tratamento farmacológico , Mastócitos/metabolismo , Receptores Histamínicos/química , Receptores Histamínicos/genéticaRESUMO
Several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. Nevertheless, many promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity and their dibasic character. Analysis of previously, as potential PET ligands synthesized compounds (ST-889, ST-928) revealed promising results concerning physicochemical properties and drug-likeness. Herein, the synthesis, the evaluation of the binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties of further novel benzylpiperidine variations on H3R antagonists is described. Due to the introduction of various small hydrophilic moieties in the structure, drug-likeness parameters have been improved. For instance, compound 12 (ST-1032) showed in addition to high affinity at the H3R (pKi (hH3R)=9.3) clogS, clogP, LE, LipE, and LELP values of -2.48, 2.18, 0.44, 7.14, and 4.95, respectively. Also, the keto derivative 5 (ST-1703, pKi (hH3R)=8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos/síntese química , Humanos , Cinética , Ligantes , Piperidinas/síntese química , Ligação Proteica , Receptores Histamínicos H3/químicaRESUMO
This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/prevenção & controle , Colágeno , Cães , Desenho de Fármacos , Descoberta de Drogas , Histamina , Indicadores e Reagentes , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Moleculares , Prurido/induzido quimicamente , Prurido/prevenção & controle , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos , Receptores Histamínicos H4 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Antihistamines play an important role in medicine when it comes to relieving seasonal or non-seasonal rhinitis, the common cold, and itching. They have also shown many various combinations of pharmacological properties such as anti-inflammatory and analgesic activities. Phenothiazines and ethylenediamines are 2 important classes of antihistamines with analgesic activities in addition to other pharmacological effects. In this study, some new derivatives of these compounds (V-IX) were synthesized and their antinociceptive behaviors were examined by pharmacological tests. The results indicated that new analogue with methyl groups produced a better analgesic activity than chlorine atoms but less than III (without any substitutions) in ethylenediamine class. Also in phenothiazine class, adding pyrimidine and pyridine substituted showed the better analgesic activity compared to other groups. Moreover, the analgesic activities proved that dimethylamine is the best group in amino alkyl side chain of these molecules relative to the substituted piperazines in new analogues.