RESUMO
The synthesis of a series of 2-amidomethylated pyridines (3-8) was investigated, starting from 4-chloro-3-fluoropyridine. Kinetic deprotonation at -75 °C followed by reaction with DMF gave 2-formyl-4-chloro-3-fluoropyridine 10 regioselectively, which was converted to 2-aminomethyl analogue 1 via sulfinamide 2. Alternatively, Minisci-type amidomethylation under Ag+/persulfate or photoredox-mediated conditions using a series of amino acid derivatives gave (3-8, 19, and 34) in 30-74% yield and isomer ratios in the range 6.7:1 to >50:1. The latter methods gave overall yields similar to that of the deprotonation approach, but were shorter and more amenable to scale-up. In particular, N-Boc analogue 8 was obtained in a single step. The amidomethylations of another six 3-fluoropyridines under the photoredox conditions were briefly examined.
RESUMO
New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.
Assuntos
Inibidores da Captação Adrenérgica/química , Norepinefrina , Piperazinas/química , Inibidores Seletivos de Recaptação de Serotonina/química , Incontinência Urinária por Estresse/tratamento farmacológico , Inibidores da Captação Adrenérgica/metabolismo , Inibidores da Captação Adrenérgica/farmacocinética , Animais , Cães , Humanos , Piperazinas/metabolismo , Piperazinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Inibidores da Captação Adrenérgica/química , Anilidas/química , Benzamidas/química , Sistema Nervoso Central/metabolismo , Pirrolidinas/química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacocinética , Anilidas/síntese química , Anilidas/farmacologia , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Linhagem Celular , Cães , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/farmacocinética , Humanos , Norepinefrina/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Ratos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.
Assuntos
Aminas/farmacologia , Hepatócitos/efeitos dos fármacos , Norepinefrina/antagonistas & inibidores , Éteres Fenílicos/farmacologia , Piridinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Aminas/síntese química , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Químicos , Éteres Fenílicos/síntese química , Piridinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship and the synthesis of novel N-benzyl-N-(pyrrolidin-3-yl)carboxamides as dual serotonin (5-HT) and noradrenaline (NA) monoamine reuptake inhibitors are described. Compounds such as 18 exhibited dual 5-HT and NA reuptake inhibition, good selectivity over dopamine (DA) reuptake inhibition and drug-like physicochemical properties consistent with CNS target space. Compound 18 was selected for further preclinical evaluation.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Norepinefrina/análise , Pirrolidinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Serotonina/análise , Amidas/química , Animais , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Inibidores do Citocromo P-450 CYP2D6 , Cães , Inibidores da Captação de Dopamina/farmacologia , Desenho de Fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Conformação Molecular , Pirrolidinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
In this article we describe a radically different industry-academia collaboration between the School of Chemistry, University of Nottingham, and GlaxoSmithKline (GSK), aiming to train students in research and give them an insight into medicinal chemistry as practiced in industry. The project concerns the discovery of potent and selective αvß6 integrin antagonists to treat idiopathic pulmonary fibrosis; the synthetic chemistry is performed by a group of ten final-year undergraduates and the biological and physicochemical screening data are generated by GSK. The project planning, organisation and operation are discussed, together with some of the challenges and rewards of working with undergraduates.
Assuntos
Descoberta de Drogas , Indústria Farmacêutica , Universidades , Pesquisa Biomédica , Humanos , EstudantesRESUMO
The integrin αvß6 is a potential target for treatment of idiopathic pulmonary fibrosis (IPF). Equilibrium dialysis (ED) was investigated for its ability to report ligand binding in an αvß6 inhibitor screening assay. As a preliminary experiment, an established peptidomimetic inhibitor of the integrin was dialyzed against αvß6, and the fraction bound (f b) and percentage saturation determined by liquid chromatography-mass spectrometry (LC-MS) analysis. Quantitation of the inhibitor in the two chambers of the ED cartridge revealed an uneven distribution in the presence of αvß6, corresponding to near saturation binding to the protein (93 ± 3%), while the control (without integrin) showed an equal partitioning of the inhibitor on either side of the dialysis membrane. A competitive ED assay with a 12 component mixture of antagonists was conducted, and the results compared with an established cell adhesion assay for quantifying αvß6 inhibition of individual antagonists. Compounds clustered into three groupings: those with pIC 50 values between ca. 5.0 and 5.5, which possessed ED f b values indistinguishable from the controls, those with pIC 50s of 6.5 ± 0.2, which exhibited detectable integrin binding (f b 13-25%) in the ED assay, and a single compound of pIC 50 7.2 possessing an f b value of 38%. A good correlation between ED-derived f b and pIC 50 was observed despite the two assays utilizing quite different outputs. These results demonstrate that ED with LC-MS detection shows promise as a rapid αvß6 integrin antagonist screening assay for mixtures of putative ligands.
RESUMO
The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The overexpression of MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with nonhealing wounds, whereas active MMPs-1, -2, -9, and -14 are required for normal wound healing to occur. We describe the synthesis and enzyme inhibition profile of (3R)-3-[([(1S)-2,2-dimethyl-1-(([(1S)-2-methoxy-1-phenylethyl]amino)carbonyl)propyl]amino)carbonyl]-6-(3-methyl-4-phenylphenyl)hexanoic acid (UK-370,106, 7), which is a potent inhibitor of MMP-3 (IC(50) = 23 nM) with >1200-fold weaker potency vs MMP-1, -2, -9, and -14. MMP-13, which may also contribute to the pathology of chronic wounds, was inhibited about 100-fold less potently by compound 7. Compound 7 potently inhibited cleavage of [(3)H]-fibronectin by MMP-3 (IC(50) = 320 nM) but not cleavage of [(3)H]-gelatin by either MMP-2 or -9 (up to 100 microM). Compound 7 had little effect, at MMP-3 selective concentrations, on keratinocyte migration over a collagen matrix in vitro, which is a model of the re-epithelialization process. Following iv (rat) or topical administration to dermal wounds (rabbit), compound 7 was cleared rapidly (t(1/2) = 23 min) from plasma, but slowly (t(1/2) approximately 3 days) from dermal tissue. In a model of chronic dermal ulcers, topical administration of compound 7 for 6 days substantially inhibited MMP-3 ex vivo. These data suggest compound 7 is sufficiently potent to inhibit MMP-3-mediated matrix degradation while leaving unaffected cellular migration mediated by MMPs 1, 2, and 9. These properties make compound 7 a suitable candidate for progression to clinical trials in human chronic dermal wounds, such as venous ulcers.
Assuntos
Caproatos/síntese química , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Dermatopatias/tratamento farmacológico , Úlcera/tratamento farmacológico , Valina/síntese química , Administração Cutânea , Animais , Caproatos/química , Caproatos/farmacologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Doença Crônica , Fibronectinas/química , Gelatina/química , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/fisiologia , Masculino , Metaloproteinase 3 da Matriz/química , Compostos Policíclicos , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Coelhos , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/enzimologia , Dermatopatias/patologia , Estereoisomerismo , Relação Estrutura-Atividade , Úlcera/enzimologia , Úlcera/patologia , Valina/análogos & derivados , Valina/química , Valina/farmacologiaRESUMO
Antagonism of αvß6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvß3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvß6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvß3, αvß5, αvß6, and αvß8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvß3 and αvß5.
RESUMO
In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.
Assuntos
Química Farmacêutica/educação , Desenho de Fármacos , Descoberta de Drogas/métodos , Currículo , Indústria Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Inibidores de Fosfoinositídeo-3 Quinase , SolubilidadeRESUMO
A series of N-benzyl-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine monoamine reuptake inhibitors are described. Selective dual 5-HT and NA reuptake inhibition was achieved, and analogues with weak CYP2D6 inhibition, good human in vitro metabolic stability and wide ligand selectivity, such as 12b, were identified.
Assuntos
Química Farmacêutica/métodos , Inibidores do Citocromo P-450 CYP2D6 , Norepinefrina/antagonistas & inibidores , Pirrolidinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Aminas/química , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Ligantes , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Modelos Químicos , Conformação Molecular , Pirrolidinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.