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1.
J Med Chem ; 64(8): 5099-5122, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33787273

RESUMO

A known zwitterionic, heterocyclic P2Y14R antagonist 3a was substituted with diverse groups on the central phenyl and terminal piperidine moieties, following a computational selection process. The most potent analogues contained an uncharged piperidine bioisostere, prescreened in silico, while an aza-scan (central phenyl ring) reduced P2Y14R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (32; MRS4654; IC50, 15 nM) and less active phenylamide-containing (33) scaffolds. Thus, a zwitterion was nonessential for receptor binding, and molecular docking and dynamics probed the hydroxymethylisoxazole interaction with extracellular loops. Also, amidomethyl ester prodrugs were explored to reversibly block the conserved carboxylate group to provide neutral analogues, which were cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application.


Assuntos
Piperidinas/química , Antagonistas do Receptor Purinérgico P2/química , Receptores Purinérgicos P2/metabolismo , Animais , Sítios de Ligação , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuralgia/tratamento farmacológico , Piperidinas/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Antagonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2/genética , Solubilidade , Relação Estrutura-Atividade , Triazóis/química
2.
Eur J Med Chem ; 216: 113313, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667846

RESUMO

P2Y14 nucleotide receptor plays important roles in series of physiological and pathologic events especially associated with immune and inflammation. Based on the 3-amide benzoic acid scaffold reported by our group previously, a series of 5-aryl-3-amide benzoic acid derivatives were designed as novel P2Y14 antagonists with improved pharmacokinetic properties. Among which compound 11m showed most potent P2Y14 antagonizing activity with an IC50 value of 2.18 nM, furnishing greatly improved water solubility and bioavailability compared with PPTN. In MSU-induced acute gouty arthritis model in mice, 11m exerted promising in vivo efficacy in alleviating mice paw swelling and inflammatory infiltration. Mechanistically, compound 11m notably blocked pyroptosis of macrophages through inhibiting NLRP3 inflammasome activation. This work may contribute to the identification of potential therapeutic agents to intervene in acute gouty arthritis.


Assuntos
Ácido Benzoico/química , Desenho de Fármacos , Antagonistas do Receptor Purinérgico P2/síntese química , Receptores Purinérgicos P2Y/química , Amidas/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/patologia , Ácido Benzoico/metabolismo , Ácido Benzoico/farmacologia , Ácido Benzoico/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antagonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/farmacologia , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Piroptose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y/metabolismo , Solubilidade , Relação Estrutura-Atividade
3.
J Med Chem ; 63(17): 9563-9589, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32787142

RESUMO

Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y14 receptor (P2Y14R) antagonists were synthesized, and affinity was measured in P2Y14R-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y14R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC50 ≈ 20 nM at hP2Y14R/mP2Y14R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y14R antagonist structure-activity relationship, introducing diverse physical-chemical properties.


Assuntos
Desenho de Fármacos , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacologia , Receptores Purinérgicos P2/metabolismo , Triazóis/química , Triazóis/farmacologia , Animais , Células HEK293 , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuralgia/tratamento farmacológico , Conformação Proteica , Antagonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Receptores Purinérgicos P2/química , Solubilidade , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/uso terapêutico
4.
J Med Chem ; 61(11): 4860-4882, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29767967

RESUMO

The P2Y14 receptor (P2Y14R) mediates inflammatory activity by activating neutrophil motility, but few classes of antagonists are known. We have explored the structure-activity relationship of a 3-(4-phenyl-1 H-1,2,3-triazol-1-yl)-5-(aryl)benzoic acid antagonist scaffold, assisted by docking and molecular dynamics (MD) simulation at a P2Y14R homology model. A computational pipeline using the High Throughput MD Python environment guided the analogue design. Selection of candidates was based upon ligand-protein shape and complementarity and the persistence of ligand-protein interactions over time. Predictions of a favorable substitution of a 5-phenyl group with thiophene and an insertion of a three-methylene spacer between the 5-aromatic and alkyl amino moieties were largely consistent with empirical results. The substitution of a key carboxylate group on the core phenyl ring with tetrazole or truncation of the 5-aryl group reduced affinity. The most potent antagonists, using a fluorescent assay, were a primary 3-aminopropyl congener 20 (MRS4458) and phenyl p-carboxamide 30 (MRS4478).


Assuntos
Desenho de Fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacologia , Receptores Purinérgicos P2/metabolismo , Aminas/química , Animais , Células CHO , Cricetulus , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacocinética , Humanos , Simulação de Dinâmica Molecular , Conformação Proteica , Antagonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/farmacocinética , Receptores Purinérgicos P2/química , Relação Estrutura-Atividade
5.
J Med Chem ; 57(17): 7293-316, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25075638

RESUMO

In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.


Assuntos
Indóis/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2/farmacologia , Piridazinas/farmacologia , Receptores Purinérgicos P2Y12/metabolismo , Síndrome Coronariana Aguda/prevenção & controle , Difosfato de Adenosina/farmacologia , Administração Oral , Animais , Ligação Competitiva , Células CHO , Cricetinae , Cricetulus , Humanos , Indóis/síntese química , Indóis/metabolismo , Injeções Intravenosas , Masculino , Modelos Químicos , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/metabolismo , Antagonistas do Receptor Purinérgico P2/síntese química , Antagonistas do Receptor Purinérgico P2/metabolismo , Piridazinas/síntese química , Piridazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y12/genética , Trombose/prevenção & controle
6.
Pharm Pat Anal ; 3(1): 53-64, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24354979

RESUMO

This review provides a concise summary of the molecular properties of the ligand-gated P2X receptors, in particular those containing the X3 subunit, as well as an overview comprising the most important patent applications on P2X3 and P2X2/3 receptor antagonists published since 2001. This review is mainly focused on small molecules with P2X3 and/or P2X2/3 antagonist properties. The most important classes of the patented compounds and conditions frequently claimed as their therapeutic targets are also discussed. Moreover, biological activity data from the cited patents and general prediction of druglikeness of the claimed compounds are also provided.


Assuntos
Patentes como Assunto , Antagonistas do Receptor Purinérgico P2/metabolismo , Receptores Purinérgicos P2X2/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Animais , Sistemas de Liberação de Medicamentos/tendências , Humanos , Patentes como Assunto/legislação & jurisprudência , Ligação Proteica/fisiologia , Antagonistas do Receptor Purinérgico P2/administração & dosagem , Antagonistas do Receptor Purinérgico P2/química
7.
PLoS One ; 8(11): e79213, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24223907

RESUMO

P2X3 receptors (P2XRs), as members of the purine receptor family, are deeply involved in chronic pain sensation and therefore, specific, competitive antagonists are of great interest for perspective pain management. Heretofore, Schild plot analysis has been commonly used for studying the interaction of competitive antagonists and the corresponding receptor. Unfortunately, the steady-state between antagonist and agonist, as a precondition for this kind of analysis, cannot be reached at fast desensitizing receptors like P2X3R making Schild plot analysis inappropriate. The aim of this study was to establish a new method to analyze the interaction of antagonists with their binding sites at the rapidly desensitizing human P2X3R. The patch-clamp technique was used to investigate the structurally divergent, preferential antagonists A317491, TNP-ATP and PPADS. The P2X1,3-selective α,ß-methylene ATP (α,ß-meATP) was used as an agonist to induce current responses at the wild-type (wt) P2X3R and several agonist binding site mutants. Afterwards a Markov model combining sequential transitions of the receptor from the closed to the open and desensitized mode in the presence or absence of associated antagonist molecules was developed according to the measured data. The P2X3R-induced currents could be fitted correctly with the help of this Markov model allowing identification of amino acids within the binding site which are important for antagonist binding. In conclusion, Markov models are suitable to simulate agonist antagonist interactions at fast desensitizing receptors such as the P2X3R. Among the antagonists investigated, TNP-ATP and A317491 acted in a competitive manner, while PPADS was identified as a (pseudo)irreversible blocker.


Assuntos
Modelos Biológicos , Agonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Sítios de Ligação/genética , Ligação Competitiva/efeitos dos fármacos , Interações Medicamentosas , Células HEK293 , Humanos , Cinética , Cadeias de Markov , Potenciais da Membrana/efeitos dos fármacos , Mutação , Técnicas de Patch-Clamp , Fenóis/metabolismo , Fenóis/farmacologia , Compostos Policíclicos/metabolismo , Compostos Policíclicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Agonistas do Receptor Purinérgico P2/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/metabolismo , Fosfato de Piridoxal/farmacologia , Receptores Purinérgicos P2X3/genética
8.
J Immunol ; 188(1): 436-44, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22102722

RESUMO

Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y(6) receptors, stimulated normal human keratinocytes (NHK) to produce IL-1α, IL-8/CXCL8, and IL-6. P2Y(6) receptor expression increased in MSU-stimulated NHK. Both P2Y(6)-specific antagonist and P2Y(6) antisense oligonucleotides significantly inhibited the production of IL-1α, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y(6)-specific antagonist completely inhibited the MSU-induced production of IL-1ß by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y(6)-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y(6) receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.


Assuntos
Antioxidantes/efeitos adversos , Queratinócitos/imunologia , Psoríase/imunologia , Antagonistas do Receptor Purinérgico P2/imunologia , Transdução de Sinais/efeitos dos fármacos , Ácido Úrico/efeitos adversos , Animais , Antioxidantes/farmacologia , Linhagem Celular , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Gota/imunologia , Gota/metabolismo , Gota/patologia , Humanos , Hiperuricemia/imunologia , Hiperuricemia/metabolismo , Hiperuricemia/patologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Peritonite/imunologia , Peritonite/metabolismo , Peritonite/patologia , Psoríase/induzido quimicamente , Psoríase/metabolismo , Psoríase/patologia , Antagonistas do Receptor Purinérgico P2/metabolismo , Receptores Purinérgicos P2 , Transdução de Sinais/imunologia , Ácido Úrico/farmacologia
9.
Expert Opin Investig Drugs ; 20(7): 897-915, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21510825

RESUMO

INTRODUCTION: The P2X7 receptor (P2X7R) has an important role in inflammation and immunity, but until recently, clinical application has been limited by a lack of specific antagonists. Recent studies using P2X7R knockout mice and specific receptor antagonists have shown that the P2X7R is an important therapeutic target in inflammatory diseases. AREAS COVERED: We have reviewed the current literature on the role of the P2X7R in inflammatory diseases, focusing on potential therapeutic applications of selective P2X7R antagonists as anti-inflammatory agents. Particular emphasis has been placed on the potential role of P2X7R in common inflammatory diseases. The latest developments in Phase I and II clinical trials of P2X7R antagonists are covered. EXPERT OPINION: Recent studies using gene knockout mice and selective P2X7R antagonists suggest that P2X7R is a viable therapeutic target for inflammatory diseases. However, efficacious P2X7R antagonists for use in clinical studies are still at an early stage of development. Future challenges include: identifying potential toxicity and side effects of treatment, timing of treatment initiation and its duration in chronic inflammatory conditions, optimum dosage and development of a functional assay for P2X7R that would help to guide treatment.


Assuntos
Mediadores da Inflamação/uso terapêutico , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Receptores Purinérgicos P2X7/metabolismo , Animais , Ensaios Clínicos como Assunto/métodos , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Antagonistas do Receptor Purinérgico P2/metabolismo , Resultado do Tratamento
10.
Mol Pharmacol ; 79(4): 649-61, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21191044

RESUMO

P2X2 receptors are members of the ATP-gated P2X family of cation channels, and they participate in neurotransmission in sympathetic ganglia and interneurons. Here, we identified 7,7'-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,6-disulfonic acid) tetrasodium salt (NF770) as a nanomolar-potent competitive P2X2 receptor antagonist within a series of 139 suramin derivatives. Three structural determinants contributed to the inhibition of P2X2 receptors by NF770: 1) a "large urea" structure with two symmetric phenylenecarbonylimino groups; 2) attachment of the naphthalene moiety in position 7,7'; and 3) the specific position of two sulfonic acid groups (3,3'; 6,6') and of one methoxy group (1,1') at the naphthalene moiety. This structure-activity relationship was interpreted using a rat P2X2 homology model based on the crystal structure of the closed zebrafish P2X4 receptor. Docking of the suramin derivatives into the modeled ATP-binding pocket provides a uniform explanation for the observed differences in inhibitory potencies. Changes in the chemical structure that increase the inhibitory potency of the suramin derivatives improved the spatial orientation within the ATP-binding pocket to allow for stronger polar interactions of functional groups with Gly72, Glu167, or Arg290. Gly72 is responsible for the orientation of the methoxy group close to Arg290 or Glu167. Combined mutational and functional analysis confirmed that residues Gly72 and Glu167 are as important for ATP binding as Arg290, the ATP-binding role of which has been shown in previous studies. The in silico prediction of Gly72 and Glu167 as ATP-binding residues strongly supports the validity of our homology docking.


Assuntos
Antagonistas do Receptor Purinérgico P2/metabolismo , Receptores Purinérgicos P2X2/genética , Receptores Purinérgicos P2X2/metabolismo , Animais , Sítios de Ligação/genética , Cristalografia por Raios X , Feminino , Ácido Glutâmico/genética , Ácido Glutâmico/metabolismo , Glicina/genética , Glicina/metabolismo , Ligantes , Mutagênese Sítio-Dirigida , Valor Preditivo dos Testes , Ligação Proteica/genética , Ratos , Receptores Purinérgicos P2X2/fisiologia , Homologia de Sequência de Aminoácidos , Suramina/metabolismo
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