RESUMO
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/síntese química , Broncodilatadores/síntese química , Antagonistas Muscarínicos/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Triazóis/síntese química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Disponibilidade Biológica , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacocinética , Broncodilatadores/farmacologia , Células CHO , Cricetulus , Cães , Humanos , Ipratrópio/farmacologia , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Ratos , Receptor Muscarínico M3/antagonistas & inibidores , Xinafoato de Salmeterol/farmacologia , Brometo de Tiotrópio/farmacologia , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
Assuntos
Azetidinas/síntese química , Broncodilatadores/síntese química , Ácidos Difenilacéticos/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Muscarínico M3/antagonistas & inibidores , Administração por Inalação , Animais , Azetidinas/química , Azetidinas/farmacologia , Broncodilatadores/química , Broncodilatadores/farmacologia , Células CHO , Linhagem Celular , Permeabilidade da Membrana Celular , Cricetinae , Cricetulus , Ácidos Difenilacéticos/química , Ácidos Difenilacéticos/farmacologia , Cães , Feminino , Cobaias , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Cinética , Masculino , Microssomos Hepáticos/metabolismo , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ensaio Radioligante , Ratos , Receptor Muscarínico M3/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
This paper describes the successful design and development of dual pharmacology ß-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Desenho de Fármacos , Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Animais , Compostos Benzidrílicos/administração & dosagem , Cresóis/administração & dosagem , Quimioterapia Combinada , Cobaias , Estrutura Molecular , Antagonistas Muscarínicos/administração & dosagem , Fenilpropanolamina/administração & dosagem , Tartarato de TolterodinaRESUMO
A novel series of potent and selective sulfonamide derived ß(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/síntese química , Asma/tratamento farmacológico , Benzenoacetamidas/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Sulfonamidas/síntese química , Administração por Inalação , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Benzenoacetamidas/farmacocinética , Benzenoacetamidas/farmacologia , Broncoconstrição/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Cães , Feminino , Cobaias , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Fígado/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Ratos , Estereoisomerismo , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/fisiopatologiaRESUMO
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Assuntos
Agonistas do Receptor A2 de Adenosina , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adenosina/análogos & derivados , Adenosina/química , Administração por Inalação , Adolescente , Adulto , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Fenetilaminas/química , Purinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.
Assuntos
Agonistas do Receptor A2 de Adenosina , Adenosina/análogos & derivados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adenosina/farmacocinética , Adenosina/farmacologia , Administração por Inalação , Administração Oral , Aminas/farmacocinética , Aminas/farmacologia , Animais , Cobaias , Humanos , Pulmão/metabolismo , Fenetilaminas/farmacocinética , Fenetilaminas/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Inflammation is a hallmark of inflammatory bowel disease (IBD), and elevation of cAMP levels can inhibit the pro-inflammatory and tissue-destructive properties of leukocytes. Phosphodiesterase 4 (PDE4) is the predominant enzyme that metabolizes cAMP in inflammatory cells, and the anti-inflammatory and immunomodulatory potential of PDE4 inhibitors in human leukocytes, endothelium and epithelium is well documented. Although PDE4 inhibitors have been investigated as treatments for several inflammatory diseases, this has focused mainly on asthma and chronic obstructive disease (COPD). Historically, their clinical utility has been limited by nausea and emesis. However, the PDE4 inhibitors cilomilast and roflumilast have recently shown efficacy in asthma and COPD, with a reduced propensity to cause nausea and emesis. In this review, we summarize for the first time the evidence that PDE4 inhibitors might have therapeutic benefit in IBD, and discuss mechanisms of action beyond the inhibition of inflammatory cells.