RESUMO
The optimisation of two series of 4-hydroxybenzothiazolone derived ß2-adrenoceptor agonists, bearing α-substituted cyclopentyl and ß-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting ß2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Benzotiazóis/administração & dosagem , Benzotiazóis/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/química , Animais , Benzotiazóis/química , Relação Dose-Resposta a Droga , Cobaias , Estrutura MolecularRESUMO
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.
Assuntos
Aminopiridinas/química , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Administração Oral , Aminopiridinas/metabolismo , Aminopiridinas/uso terapêutico , Animais , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/antagonistas & inibidores , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Deleção de Genes , Meia-Vida , Humanos , Ligação Proteica , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-AtividadeRESUMO
The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Tiazóis/uso terapêutico , Administração por Inalação , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacologia , Tiazóis/farmacologiaRESUMO
The synthesis of two series of 4'-aza-carbocyclic nucleosides are described in which the 4'-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A(2A) receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively.
Assuntos
Agonistas do Receptor A2 de Adenosina , Compostos Aza/síntese química , Ácidos Carboxílicos/síntese química , Nucleosídeos/síntese química , Nucleotídeos de Pirimidina/síntese química , Animais , Compostos Aza/metabolismo , Compostos Aza/farmacologia , Células CHO , Ácidos Carboxílicos/metabolismo , Ácidos Carboxílicos/farmacologia , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Nucleosídeos/metabolismo , Nucleosídeos/farmacologia , Nucleotídeos de Pirimidina/metabolismo , Nucleotídeos de Pirimidina/farmacologia , Ratos , Receptor A2A de Adenosina/metabolismoRESUMO
Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.
Assuntos
Ácidos Cicloexanocarboxílicos/química , Naftiridinas/química , Inibidores da Fosfodiesterase 4/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Náusea/induzido quimicamente , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/farmacologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Termodinâmica , Vômito/induzido quimicamenteRESUMO
The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.
Assuntos
Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/uso terapêutico , Ratos , Solubilidade , Vômito/tratamento farmacológicoRESUMO
The synthesis and SAR of 5-heterocycle-substituted aminothiazole adenosine receptor antagonists is described. Several compounds show high affinity and selectivity for the A2B and A3 receptors. One compound (5f) shows good ADME properties in the rat and as such may be an important new compound in testing the current hypotheses proposing a therapeutic role for a dual A2B/A3 antagonist in allergic diseases.