RESUMO
The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of ß-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aß peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.
Assuntos
Fármacos Neuroprotetores , Receptores sigma , Receptor Sigma-1 , Animais , Receptores sigma/agonistas , Receptores sigma/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Ratos , Humanos , Masculino , Relação Estrutura-Atividade , Peptídeos beta-Amiloides/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Transtornos da Memória/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Pirimidinonas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/química , Ratos Wistar , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismoRESUMO
The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the µ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Cavα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several inâ vivo pain models as well as a reduced side-effect profile in relation to morphine.
Assuntos
Analgésicos , Canais de Cálcio , Dor , Receptores Opioides mu , Animais , Humanos , Masculino , Ratos , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/síntese química , Canais de Cálcio/metabolismo , Canais de Cálcio/química , Relação Dose-Resposta a Droga , Ligantes , Estrutura Molecular , Dor/tratamento farmacológico , Receptores Opioides mu/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The synthesis and pharmacological activity of a new series of isoxazolylpyrimidines as sigma-2 receptor (σ2R) ligands are reported. Modification of a new hit retrieved in an HTS campaign allowed the identification of the compound WLB-89462 (20c) with good σ2R affinity (Ki = 13 nM) and high selectivity vs both the σ1R (Ki = 1777 nM) and a general panel of 180 targets. It represents one of the first σ2R ligands with drug-like properties, linked to a good physicochemical and ADMET profile (good solubility, no CYP inhibition, good metabolic stability, high permeability, brain penetration, and high oral exposure in rodents). Compound 20c shows neuroprotective activity in vitro and improves short-term memory impairment induced by hippocampal injection of amyloid ß peptide in rats. Together with the promising effects in the chronic models where 20c is currently being evaluated, these results pave the way toward its clinical development as a neuroprotective agent.
Assuntos
Peptídeos beta-Amiloides , Fármacos Neuroprotetores , Animais , Ratos , Ligantes , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that Sig-1R is a target to prevent MN degeneration. In this study, two novel synthesized Sig-1R ligands, coded EST79232 and EST79376, from the same chemical series, with the same scaffold and similar physicochemical properties but opposite functionality on Sig-1R, were evaluated as neuroprotective compounds to prevent MN degeneration. We used an in vitro model of spinal cord organotypic cultures under chronic excitotoxicity and two in vivo models, the spinal nerve injury and the superoxide dismutase 1 (SOD1)G93A mice, to characterize the effects of these Sig-1R ligands on MN survival and modulation of glial reactivity. The antagonist EST79376 preserved MNs in vitro and after spinal nerve injury but was not able to improve MN death in SOD1G93A mice. In contrast, the agonist EST79232 significantly increased MN survival in the three models of MN degeneration evaluated and had a mild beneficial effect on motor function in SOD1G93A mice. In vivo, Sig-1R ligand EST79232 had a more potent effect on preventing MN degeneration than EST79376. These data further support the interest in Sig-1R as a therapeutic target for neurodegeneration.
Assuntos
Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/metabolismo , Animais , Modelos Animais de Doenças , Ligantes , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neuroproteção , Receptores sigma , Medula Espinal/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/metabolismo , Receptor Sigma-1RESUMO
The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido[4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Cavα2δ-1 versus Cavα2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.
RESUMO
The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.
Assuntos
Azepinas/farmacologia , Canais de Cálcio/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Animais , Azepinas/síntese química , Azepinas/metabolismo , Células CHO , Cricetulus , Células HEK293 , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/metabolismo , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored in vitro. EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σ1R) antagonism and µ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity.Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones.Fraction unbound was determined due to its impact in interactions, a considerable proportion of EST73502 being available.EST73502 showed a low potential for CYP inhibition, except for CYP2D6 that showed time-dependent inhibition.No induction potential was found for CYP1A2 and 3A4, while CYP2B6 was induced at high concentration.EST73502 seemed to be a potential efflux transporter substrate (efflux ratio ≥ 2) but a negligible in vivo impact would be expected due to its high solubility and permeability in Caco-2 cells. P-gp inhibition was observed while no BCRP inhibition was detected.Preliminary in vitro interaction studies suggested that neither CYPs nor efflux transporters interactions would preclude further development of EST73502 to thoroughly assess the clinical relevance of these findings.
Assuntos
Preparações Farmacêuticas , Receptores sigma , Células CACO-2 , Interações Medicamentosas , Humanos , Receptores Opioides mu/agonistas , Receptor Sigma-1RESUMO
EST64401 and EST64514 are two selective sigma-1 receptor ligands that showed a good profile in a lead optimization process for oral pain treatment. Their potential for pharmacokinetic-based drug-drug interactions was assessed to anticipate clinical interactions.Both compounds showed a low potential for CYP inhibition with percentages of inhibition <50% at 1 µM in recombinant human CYPs (CYP1A2, 2C9, 2C19, 2D6 and 3A4) and IC50 ≥75 µM for CYP3A4 and 2D6 in human liver microsomes.No CYP induction was observed for CYP1A2, 2B6 and 3A4 at concentrations ≤25 µM (EST64401) or ≤50 µM (EST64514) in human hepatocytes using as endpoints CYP activities and mRNA levels.More than one enzyme participated in compound metabolism. The main enzymes involved were CYP3A4 for EST64401 and CYP2D6 besides CYP3A4 for EST64514.Neither EST64401 nor EST64514 seemed to be substrates of P-gp or BCRP in Caco-2 cells (efflux ratio ≤2). Transporter inhibition was observed at concentrations ≥20 µM; EST64401 only inhibiting P-gp at higher concentrations (≥125 µM).Preliminary in vitro interaction studies suggest a similar profile for EST64401 and EST64514. Therefore, other properties will have to be considered for compound differentiation and selection for further development.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Células CACO-2 , Interações Medicamentosas , Humanos , Microssomos Hepáticos , Proteínas de Neoplasias , Receptores sigma , Receptor Sigma-1RESUMO
EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug-drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. EST64454 showed a low potential for CYP inhibition (IC50 between 100 and 1000 µM) and as time-dependent inhibitor (IC50 shift mainly around 1). CYP induction studies with HepaRG™ cells revealed no CYP induction at concentrations ≤50 µM, as shown by the CYP1A2, 3A4 and 2B6 activities measured. Reaction phenotyping was assessed after incubation with recombinant human enzymes. Although a very low metabolism was observed, several enzymes catalyzed the formation of metabolites, including CYP3A4, 2C19 and flavin monooxygenases (FMO) 1 and 3. EST64454 was not a P-glycoprotein (P-gp) substrate and was highly permeable in Caco-2 cells. P-gp inhibition was only observed at 200 µM, the highest concentration studied. Preliminary studies suggest that neither CYP nor P-gp interaction of EST64454 would be of any concern for further development. At later stages, the interaction kinetics and the clinical relevance of these findings will be thoroughly evaluated.
Assuntos
Analgésicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Receptores sigma/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Analgésicos/farmacocinética , Linhagem Celular , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Feminino , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Receptor Sigma-1RESUMO
Because of their neuroprotective potential, GluN2B-selective ligands are of great interest for the treatment of various neurological and neurodegenerative disorders. Fluorinated benzo[7]annulen-7-amines, capable for PET, were synthesized by combining fluorinated phenylalkylamines with differently substituted ketones. Relationships between substitution pattern and GluN2B affinity as well as selectivity towards σ1 and σ2 receptors were investigated. Two promising ligands (18a and 20c) were selected for further pharmacological evaluation. Besides a slight serotonin transporter (SERT), norepinephrine transporter (NET), and hERG affinity, they did not show interaction with other targets. Furthermore, the pKa value of a set fluorinated ligands, bearing the fluorine atom in different positions, was determined.
Assuntos
Aminas/síntese química , Aminas/farmacologia , Halogenação , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Aminas/química , Aminas/metabolismo , Técnicas de Química Sintética , Receptores de N-Metil-D-Aspartato/metabolismo , Especificidade por SubstratoRESUMO
In order to detect novel σ receptor ligands, the rigid spiro[[2]benzopyran-1,1'-cyclohexan]-4'-one was connected with amino moieties derived from σ2 receptor preferring lead compounds resulting in mixtures of trans- and cis-configured amines 6, 18, and 27. In a four step synthesis the methyl acetals 6 were converted into fluoroethyl derivatives 13 and 30. The most promising σ2 receptor ligand is the methyl acetal 6a bearing a 2,4-dimethylbenzylamino moiety. The fluoroethyl derivatives 13c and 13d reveal high σ1 affinity but moderate selectivity over the σ2 subtype. In mice 13c and 13d showed antiallodynic activity that is stronger than that of the reference σ1 antagonist BD-1063 (34). Since the antiallodynic activity of 13c could only be partially reversed by the σ1 agonist PRE-084 (35), it is postulated that a second mechanism contributes to its overall antiallodynic effect. In contrast, the antiallodynic effect of its diastereomer 13d can be totally explained by a σ1 antagonism.
Assuntos
Hiperalgesia/tratamento farmacológico , Receptores sigma/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Técnicas de Química Sintética , Feminino , Ligantes , Camundongos , Ligação Proteica , Receptores sigma/química , Compostos de Espiro/metabolismo , Compostos de Espiro/uso terapêutico , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.
Assuntos
Analgésicos/síntese química , Analgésicos/metabolismo , Quinolinas/síntese química , Quinolinas/metabolismo , Receptores sigma/metabolismo , Analgésicos/química , Analgésicos/farmacocinética , Animais , Fenômenos Químicos , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos , Feminino , Cobaias , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Conformação Proteica , Quinolinas/química , Quinolinas/farmacocinética , Receptores sigma/química , Relação Estrutura-AtividadeRESUMO
The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.
Assuntos
Compostos de Bifenilo/química , Crotonatos/química , Inibidores Enzimáticos/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Toluidinas/química , Animais , Artrite Experimental/tratamento farmacológico , Sítios de Ligação , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/uso terapêutico , Simulação por Computador , Di-Hidro-Orotato Desidrogenase , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidroxibutiratos , Nitrilas , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-AtividadeRESUMO
Several new potent and selective A(2B) adenosine receptor antagonists have been prepared in which the aryl-amide moiety of the lead series, exemplified by 1a, has been replaced by bioisosteric bicyclic moieties. Although the majority of compounds had generally improved microsomal stability as compared to 1a, this was not translated into overall improvements in the pharmacokinetic profiles of a representative set of compounds.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Amidas/química , Anti-Inflamatórios/química , Compostos Bicíclicos com Pontes/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacocinética , Descoberta de Drogas , Humanos , Microssomos Hepáticos/metabolismo , NADP/metabolismo , Ratos , Receptor A2B de Adenosina/metabolismoRESUMO
A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Furanos/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Animais , Linhagem Celular , Cricetinae , Cricetulus , Cães , Furanos/farmacocinética , Furanos/farmacologia , Camundongos , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.
Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Pró-Fármacos/farmacologia , Sulfonas/farmacologia , Sulfóxidos/farmacologia , Animais , Cristalografia por Raios X , Ciclo-Oxigenase 1/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Sulfóxidos/síntese química , Sulfóxidos/químicaRESUMO
The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.