RESUMO
It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.
RESUMO
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Neurite (Inflamação)/tratamento farmacológico , Amidoidrolases/antagonistas & inibidores , Animais , Ácidos Araquidônicos/metabolismo , Biomarcadores , Química Encefálica/efeitos dos fármacos , Cães , Desenho de Fármacos , Descoberta de Drogas , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Humanos , Macaca mulatta , Modelos Moleculares , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.
Assuntos
Isoindóis/farmacologia , Lactamas/farmacologia , Oxazóis/farmacologia , Receptor Muscarínico M1/agonistas , Convulsões/induzido quimicamente , Regulação Alostérica , Anfetamina/farmacologia , Animais , Ataxia/induzido quimicamente , Diarreia/induzido quimicamente , Cães , Donepezila , Desenho de Fármacos , Feminino , Humanos , Indanos/farmacologia , Isoindóis/administração & dosagem , Isoindóis/síntese química , Isoindóis/toxicidade , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Oxazóis/administração & dosagem , Oxazóis/síntese química , Oxazóis/toxicidade , Piperidinas/farmacologia , Ratos Wistar , Receptor Muscarínico M1/antagonistas & inibidores , Escopolamina/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Tiadiazóis/farmacologia , Vômito/induzido quimicamenteRESUMO
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
Assuntos
Descoberta de Drogas , Ácidos Picolínicos/farmacologia , Receptor Muscarínico M1/agonistas , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ratos , Receptor Muscarínico M1/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/síntese química , Mesilato de Imatinib/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-AtividadeRESUMO
Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Indóis/química , Indóis/farmacologia , Receptor Muscarínico M1/metabolismo , Amidas/farmacocinética , Animais , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Indóis/farmacocinética , Camundongos , Simulação de Acoplamento Molecular , Receptor Muscarínico M1/agonistasRESUMO
A continuous protocol for the two-carbon homologation of esters to α,ß-unsaturated esters is described. This multireactor homologation telescopes an ester reduction, phosphonate deprotonation, and Horner-Wadsworth-Emmons olefination, thus converting a three-operation procedure into a single, uninterrupted system that eliminates the need for isolation or purification of the aldehyde intermediates. The homologated products are obtained in high yield and selectivity.
Assuntos
Alcenos/química , Organofosfonatos/química , Catálise , Técnicas de Química Combinatória , Ésteres , Estrutura Molecular , EstereoisomerismoRESUMO
A continuous flow system for the multiparameter (flow rate, temperature, residence time, stoichiometry) optimization of the DIBALH reduction of esters to aldehydes is described. Incorporating an in-line quench (MeOH), these transformations are generally complete in fewer than 60 s. Mixing of the DIBALH and ester solutions was observed to be an exceptionally critical parameter for optimum results. This system thus provides general guidelines based on the structure of the ester for selective reduction of an ester without overreduction.