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1.
Eur J Med Chem ; 264: 116036, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38101041

RESUMO

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 µM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.


Assuntos
Receptores de AMPA , Tiadiazinas , Camundongos , Animais , Receptores de AMPA/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Receptores de Ácido Caínico/metabolismo , Relação Estrutura-Atividade , Tiadiazinas/química , Regulação Alostérica
2.
Eur J Med Chem ; 250: 115221, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36863228

RESUMO

Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position.


Assuntos
Receptores de AMPA , Tiadiazinas , Camundongos , Animais , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , Receptores de AMPA/metabolismo , Tiadiazinas/farmacologia , Tiadiazinas/química , Benzotiadiazinas/farmacologia , Benzotiadiazinas/química , Tiazidas , Regulação Alostérica
3.
Bioorg Med Chem ; 16(23): 9948-56, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18980844

RESUMO

Taking into account structure-activity relationships obtained with our previous series, new diversely substituted 1,2,4-pyridothiadiazine 1,1-dioxides were designed to obtain novel AMPA potentiators. The aim of this work was focused on the improvement of lipophilicity, which is well known as a critical parameter to obtain in vivo active central nervous system agents. For this purpose, two positions on the pyridine ring were privileged to insert selected groups. Among the synthesized compounds emerged 7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide (12d), which was evaluated in two memory tests in Wistar rats and showed cognition enhancing effects after intraperitoneal injection at doses as low as 0.3mg/kg.


Assuntos
Diazóxido/farmacologia , Receptores de AMPA/efeitos dos fármacos , Tiadiazinas/síntese química , Tiadiazinas/farmacologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Animais , Diazóxido/química , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Ratos , Ratos Wistar , Receptores de AMPA/biossíntese , Receptores de AMPA/genética , Solubilidade , Relação Estrutura-Atividade , Tiadiazinas/química , Xenopus laevis , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/química
4.
J Med Chem ; 50(13): 3153-7, 2007 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-17552506

RESUMO

A series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as potentiators of AMPA receptors. Attention was paid to the impact of the substituent introduced at the 7-position of the heterocycle. The biological evaluation was achieved by measuring the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most potent compound, 4-ethyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (12a) was found to be active in an object recognition test in rats demonstrating cognition enhancing effects in vivo after oral administration.


Assuntos
Óxidos S-Cíclicos/síntese química , Receptores de AMPA/metabolismo , Tiadiazinas/síntese química , Regulação Alostérica , Animais , Benzotiadiazinas , Cognição/efeitos dos fármacos , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Desenho de Fármacos , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Técnicas In Vitro , Norepinefrina/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de AMPA/genética , Reconhecimento Psicológico/efeitos dos fármacos , Relação Estrutura-Atividade , Tiadiazinas/química , Tiadiazinas/farmacologia , Xenopus , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia
5.
ACS Chem Neurosci ; 7(3): 378-90, 2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-26771108

RESUMO

Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer's disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7-4.3 µM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 µM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure-activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency.


Assuntos
Benzotiadiazinas/química , Benzotiadiazinas/síntese química , Receptores de AMPA/metabolismo , Animais , Cristalografia por Raios X , Eletrofisiologia , Oócitos , Ratos , Receptores Ionotrópicos de Glutamato/metabolismo , Relação Estrutura-Atividade , Xenopus laevis
6.
J Med Chem ; 57(22): 9539-53, 2014 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-25375781

RESUMO

Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.


Assuntos
Benzotiadiazinas/química , Óxidos S-Cíclicos/química , Óxidos/química , Propionatos/química , Receptores de AMPA/química , Tiadiazinas/química , Sítio Alostérico , Animais , Calorimetria , Química Farmacêutica/métodos , Cristalografia por Raios X , Dimerização , Desenho de Fármacos , Eletrofisiologia , Hipocampo/efeitos dos fármacos , Humanos , Hidrogênio/química , Cinética , Camundongos , Ligação Proteica , Ratos , Ratos Wistar , Temperatura , Termodinâmica
7.
J Med Chem ; 56(20): 7838-50, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24090223

RESUMO

On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low as 0.3 mg/kg. This study validates the interest of the isosteric replacement of the benzene or pyridine nuclei by the thiophene nucleus in the ring-fused thiadiazine dioxides class of AMPA potentiators.


Assuntos
Benzotiadiazinas/farmacologia , Diazóxido/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Receptores de AMPA/agonistas , Animais , Benzotiadiazinas/química , Células Cultivadas , Cognição/efeitos dos fármacos , Óxidos S-Cíclicos/síntese química , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Diazóxido/química , Desenho de Fármacos , Agonistas de Aminoácidos Excitatórios/síntese química , Agonistas de Aminoácidos Excitatórios/química , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Modelos Químicos , Estrutura Molecular , Norepinefrina/metabolismo , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Ratos , Receptores de AMPA/metabolismo , Tiadiazinas/síntese química , Tiadiazinas/química , Tiadiazinas/farmacologia , Tiofenos/química , Xenopus laevis , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia
8.
J Med Chem ; 53(1): 147-54, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-19919106

RESUMO

The synthesis of 5-chloro-, 6-chloro-, and 8-chloro-substituted 3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their inhibitory effect on the insulin releasing process and their vasorelaxant activity was compared to that of previously reported 7-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. "5-Chloro" compounds were found to be essentially inactive on both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active on insulin-secreting cells, with the "6-chloro" derivatives emerging as the most potent drugs. Moreover, the "6-chloro" analogues exhibited less myorelaxant activity than their "7-chloro" counterparts. 8-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (25b) and 6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (19e) were further identified as K(ATP) channel openers by radioisotopic measurements conducted on insulin-secreting cells. Likewise, current recordings on HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC(50) = 80 nM) on such types of K(ATP) channels. The present work indicates that 6-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides appear to be more attractive than their previously described 7-chloro-substituted analogues as original drugs activating the SUR1/Kir6.2 K(ATP) channels.


Assuntos
Benzotiadiazinas/farmacologia , Cloro/química , Óxidos S-Cíclicos/farmacologia , Diazóxido/análogos & derivados , Diazóxido/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Benzotiadiazinas/síntese química , Benzotiadiazinas/química , Linhagem Celular , Óxidos S-Cíclicos/síntese química , Óxidos S-Cíclicos/química , Diazóxido/química , Avaliação Pré-Clínica de Medicamentos , Glucose/farmacologia , Humanos , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Estrutura Molecular , Músculo Liso Vascular/metabolismo , Canais de Potássio/metabolismo , Ratos , Estereoisomerismo
9.
J Med Chem ; 53(4): 1700-11, 2010 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-20108934

RESUMO

In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA receptors. In the present work, we focused our efforts on the insertion of mono- or polyfluoro-substituted alkyl chains at the 4-position of the thiadiazine ring in an attempt to enhance the pharmacokinetic behavior of previously described compounds. Among all the described compounds, 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, 12b, was shown to exert a strong activity on AMPA receptors in vitro and a marked cognitive-enhancing effect in vivo after oral administration to Wistar rats. Considering its in vivo activity, the metabolic degradation of 12b was studied and compared to that of its nonfluorinated analogue 9b. Taken together, results of this study clearly validated the positive impact of the fluorine atom on the alkyl chain at the 4-position of benzothiadiazine dioxides on activity and metabolic stability.


Assuntos
Benzotiadiazinas/síntese química , Óxidos S-Cíclicos/síntese química , Fármacos Atuantes sobre Aminoácidos Excitatórios/síntese química , Nootrópicos/síntese química , Receptores de AMPA/fisiologia , Administração Oral , Regulação Alostérica , Animais , Benzotiadiazinas/química , Benzotiadiazinas/farmacologia , Células Cultivadas , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/química , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Microssomos Hepáticos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nootrópicos/química , Nootrópicos/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Relação Estrutura-Atividade , Xenopus laevis
10.
Recent Pat CNS Drug Discov ; 1(3): 239-46, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18221205

RESUMO

Glutamate is the major excitatory neurotransmitter in the brain. Amongst ionotropic receptors responding to glutamate, the AMPA subtype has been considered as essential for the fast excitatory neurotransmission in the central nervous system and the expression and maintenance of long-term potentiation. As glutamate is known to be involved in many neurological and psychiatric disorders, AMPA receptors seem to represent interesting targets to develop therapeutic drugs. Hence, the enhancement of AMPA signals is an approach currently investigated for the management of Alzheimer's disease, schizophrenia or mood disorders. In particular, many efforts are being conducted in the development of AMPA positive allosteric modulators ("potentiators"), which alter the rate of receptor desensitization. The major chemical families developed as AMPA potentiators are aniracetam derivatives, cyclothiazide derivatives and biarylpropylsulfonamides derivatives.


Assuntos
Receptores de AMPA/efeitos dos fármacos , Regulação Alostérica , Animais , Benzotiadiazinas/farmacologia , Cognição/efeitos dos fármacos , Humanos , Transtornos do Humor/tratamento farmacológico , Pirrolidinonas/farmacologia , Receptores de AMPA/fisiologia , Sulfonamidas/farmacologia
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