RESUMO
Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 µg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 µg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.
Assuntos
Pneumopatias/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Quinuclidinas/uso terapêutico , Administração por Inalação , Animais , Células CHO , Cálcio/metabolismo , Carbacol/farmacologia , Antagonistas Colinérgicos/farmacologia , Cricetinae , Cricetulus , Cobaias , Cinética , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/administração & dosagem , Pletismografia , Quinuclidinas/administração & dosagem , Receptor Muscarínico M3/efeitos dos fármacos , Receptores Muscarínicos , Derivados da Escopolamina/farmacologia , Brometo de TiotrópioRESUMO
A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
Assuntos
Antagonistas Muscarínicos/síntese química , Tropanos/síntese química , Animais , Broncopatias/tratamento farmacológico , Desenho de Fármacos , Camundongos , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Relação Estrutura-Atividade , Tropanos/farmacologiaRESUMO
Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery.
Assuntos
Compostos de Bifenilo/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Antagonistas Muscarínicos/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptores Muscarínicos/química , Administração por Inalação , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Descoberta de Drogas , Humanos , Camundongos , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacocinética , Ratos , Receptores Muscarínicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.
Assuntos
Aminas/síntese química , Química Farmacêutica/métodos , Receptor Muscarínico M3/antagonistas & inibidores , Amidas/química , Aminas/farmacologia , Asma/tratamento farmacológico , Desenho de Fármacos , Elétrons , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Estrutura Molecular , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Muscarínico M3/química , Relação Estrutura-AtividadeRESUMO
A short synthesis of the non-adjacent bis-THF core of the Annonaceous acetogenin cis-sylvaticin (1) is described. C(2) Symmetrical (Z,E,E,Z)- and (E,E,E,E)-tetraenes and were synthesised in six and three steps respectively from (1E,5E,9E)-cyclododeca-1,5,9-triene. Subsequent permanganate promoted asymmetric bi-directional oxidative cyclisation of tetraene was used to create the non-adjacent bis-THF core of 1, installing seven of the nine stereogenic centres present in the natural product in a single step. Desymmetrization of the oxidative cyclisation product by mono-tosylation gave access to a C11-C32 fragment of cis-sylvaticin.
Assuntos
Furanos/química , Ciclização , Furanos/síntese química , Oxirredução , Polienos/química , EstereoisomerismoRESUMO
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Amidas/sangue , Amidas/química , Aminoácidos/genética , Aminoácidos/metabolismo , Sítios de Ligação , Compostos de Bifenilo/sangue , Compostos de Bifenilo/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Fármacos , Lipopolissacarídeos/farmacologia , Conformação Molecular , Estrutura Molecular , Naftalenos/farmacologia , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Benzamidas/sangue , Benzamidas/química , Compostos de Bifenilo/sangue , Compostos de Bifenilo/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Conformação Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/química , RatosRESUMO
In 2002, the first long-acting muscarinic antagonist, tiotropium bromide (Spiriva(®)), was launched as a once-daily bronchodilating agent for the treatment of chronic obstructive pulmonary disease. Since then, there has been intense discovery research activity in this area and, currently, several alternative inhaled long-acting muscarinic antagonists are reported under clinical development by several pharmaceutical companies. This article will review the current inhaled development candidates, as well as literature reports of the most significant preclinical chemical series specifically designed as inhaled antimuscarinic agents.
Assuntos
Broncodilatadores/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Broncodilatadores/administração & dosagem , Humanos , Peso Molecular , Antagonistas Muscarínicos/administração & dosagemRESUMO
Muscarinic acetylcholine receptor antagonists, particularly of the M(3) subtype, are useful therapeutics as bronchodilators in chronic obstructive pulmonary disease (COPD). The first long-acting muscarinic antagonist, tiotropium bromide (Spiriva(®)), was launched in 2002 and has since become established as the gold-standard muscarinic antagonist for the treatment of COPD. This review will survey the preclinical profiles of tiotropium and nine inhaled development candidates as well as literature reports of other preclinical compounds specifically designed as inhaled antimuscarinic agents for the treatment of COPD. The design strategies employed lay behind three common principles: high potency and slow reversibility at the M(3) receptor and low systemic exposure. In addition to their effectiveness as bronchodilators, the differentiation of these agents in the clinic may be linked to their potential to be utilized in combination with other therapeutics. In the long term, the emerging knowledge around the role of muscarinic antagonists in the inflammation and remodeling of the airways may also help in discriminating them.
RESUMO
IMPORTANCE TO THE FIELD: Cathepsin C (dipeptidyl peptidase I) plays a key role in the activation of several degradative enzymes linked to tissue destruction in inflammatory diseases. Thus, cathepsin C inhibitors could potentially be effective therapeutics for the treatment of such diseases as chronic obstructive pulmonary disease and cystic fibrosis. AREAS COVERED IN THIS REVIEW: Although this article focuses on cathepsin C inhibitor patents, the journal literature concerning small molecule inhibitors of the enzyme is also covered comprehensively (1981 - 2009). WHAT THE READER WILL GAIN: It is our aim to give the reader a complete overview of the cathepsin C inhibitor chemotypes that have been disclosed to date. In addition, key biological data have been included for both irreversible and reversible inhibitors. TAKE HOME MESSAGE: All known cathepsin C inhibitors are believed to have a covalent interaction with the Cys-234 residue of the enzyme. The electrophilic and sometimes peptidic nature of these molecules is associated with poor metabolic stability and is also a potential safety concern. Thus, overcoming developability issues is a serious hurdle for these compounds and there can be little doubt that this is the principal reason why no cathepsin C inhibitors appear to have reached clinical development so far.
Assuntos
Catepsina C/antagonistas & inibidores , Fibrose Cística/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Fibrose Cística/enzimologia , Fibrose Cística/fisiopatologia , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/fisiopatologia , Patentes como Assunto , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologiaRESUMO
A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.
Assuntos
Compostos Benzidrílicos/síntese química , Broncodilatadores/síntese química , Quinuclidinas/síntese química , Receptor Muscarínico M3/antagonistas & inibidores , Animais , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Disponibilidade Biológica , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/química , Broncodilatadores/farmacologia , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Camundongos , Modelos Moleculares , Contração Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Quinuclidinas/química , Quinuclidinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.
Assuntos
Compostos de Bifenilo/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Antagonistas Muscarínicos/síntese química , Tropanos/síntese química , Animais , Disponibilidade Biológica , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Broncoconstrição/efeitos dos fármacos , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Contração Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ensaio Radioligante , Ratos , Receptor Muscarínico M1/fisiologia , Receptor Muscarínico M2/fisiologia , Receptor Muscarínico M3/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , Tropanos/química , Tropanos/farmacologiaRESUMO
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Piperazinas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Administração Intranasal , Animais , Testes de Provocação Brônquica , Broncoconstritores/farmacologia , Broncodilatadores/síntese química , Broncodilatadores/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cloreto de Metacolina/farmacologia , Camundongos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In the course of our research program to develop novel muscarinic receptor antagonists for the treatment of COPD, new tropane carbamate derivatives were identified as potent anti-muscarinic agents. The synthesis, structure-activity relationships and pharmacological evaluation that led to the identification of compound 5o, are described.