RESUMO
AZD8871 is a novel muscarinic antagonist and ß 2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the ß 2-adrenoceptor over the ß 1 and ß 3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and ß 2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Triazóis/efeitos adversos , Triazóis/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Cães , Cobaias , Humanos , Masculino , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Receptor Muscarínico M2/metabolismo , Distribuição Tecidual , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Triazóis/administração & dosagem , Triazóis/farmacocinéticaRESUMO
Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.
Assuntos
Naftiridinas/síntese química , Naftiridinas/farmacologia , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/farmacologia , Administração por Inalação , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inaladores de Pó Seco , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Masculino , Naftiridinas/administração & dosagem , Neutrófilos/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/administração & dosagem , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/sangueRESUMO
LAS190792 is a novel muscarinic antagonist and ß2-adrenoceptor agonist in development for chronic respiratory diseases. This study investigated the pharmacological profile of LAS190792 in comparison to batefenterol, tiotropium, indacaterol and olodaterol. LAS190792 is potent at the human M3 receptor (pIC50: 8.8 in binding assays). It is selective for the ß2-adrenoceptor over the ß1-and ß3-adrenoceptor, and shows a functional potency in a similar range to batefenterol and LABA compounds (pEC50 in spontaneous tone isolated trachea: 9.6). The relaxant potency of LAS190792 in electrically stimulated tissue is similar to batefenterol, with an antimuscarinic activity in presence of propranolol slightly higher than batefenterol (pIC50 of 8.3 versus 7.9 in human tissue). LAS190792 exhibits a sustained duration of action in isolated tissue longer than that of batefenterol. Nebulized LAS190792 inhibits acetylcholine-induced bronchoconstriction in dog with minimal cardiac effects and sustained bronchodilation (t1/2: 13.3 h). In conclusion, these studies suggest that LAS190792 is a dual-acting muscarinic antagonist ß2-adrenoceptor agonist that has the potential to be a next generation bronchodilator with long-lasting effects and wide safety margin in humans.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Cicloexanos/farmacologia , Antagonistas Muscarínicos/farmacologia , Quinolinas/farmacologia , Tiofenos/farmacologia , Acetilcolina/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Animais , Broncoconstrição/efeitos dos fármacos , Cicloexanos/administração & dosagem , Cães , Cobaias , Meia-Vida , Humanos , Concentração Inibidora 50 , Masculino , Antagonistas Muscarínicos/administração & dosagem , Quinolinas/administração & dosagem , Receptor Muscarínico M3/antagonistas & inibidores , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/fisiopatologia , Tiofenos/administração & dosagemRESUMO
Pruritus is a major symptom of several dermatological diseases but has limited therapeutic options available. Animal models replicating the pathophysiology of pruritus are needed to support the development of new drugs. Induction of pruritus by chloroquine (CQ) in mice is widely used, although, as with similar models, it has low throughput and does not distinguish between antipruritic effects and confounding factors such as sedation. To overcome these issues, we incorporated into the model an automated system that measures both scratching and locomotor behaviour simultaneously. We combined this system with the determination of CQ levels in different tissues to understand the impact of the route of CQ administration on the pruritogenic response. We concluded that whereas oral CQ does not induce pruritus due to insufficient skin levels, the bell-shaped curve of pruritus observed following subcutaneous administration is due to toxicity at high doses. We validated the model with several drugs currently used in humans: nalfurafine, aprepitant, cyproheptadine and amitriptyline. By comparing the effects of the drugs on both scratching and locomotor activity, we concluded that nalfurafine and aprepitant can exhibit efficacy at doses devoid of central effects, whereas central effects drove the efficacy of the other two drugs. This was further confirmed using non-brain-penetrant drugs. Moreover, as anticipated, anti-inflammatory drugs showed no efficacy. In conclusion, the use of an automated integrated behavioural assessment in CQ-induced pruritus makes the assay suitable for screening purposes and allows for a correct interpretation of the antipruritic effect of the compounds evaluated.
Assuntos
Antipruriginosos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cloroquina/administração & dosagem , Modelos Animais de Doenças , Atividade Motora/efeitos dos fármacos , Prurido/fisiopatologia , Administração Oral , Amitriptilina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antidepressivos Tricíclicos/farmacologia , Aprepitanto , Cloroquina/metabolismo , Ciproeptadina/farmacologia , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfinanos/farmacologia , Morfolinas/farmacologia , Antagonistas de Entorpecentes/farmacologia , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Reconhecimento Automatizado de Padrão/métodos , Prurido/induzido quimicamente , Prurido/psicologia , Processamento de Sinais Assistido por Computador , Pele/metabolismo , Compostos de Espiro/farmacologia , Vibração , Gravação em VídeoRESUMO
Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.
Assuntos
Compostos de Bifenilo/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Piridazinas/farmacologia , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Piridazinas/síntese química , Piridazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Abediterol is a novel long-acting ß2-adrenoceptor agonist (LABA) currently in development for once-daily combination maintenance therapy of asthma and COPD. This study investigated the preclinical profile of abediterol in terms of affinity, potency, selectivity, duration of action and cardiac effects in comparison to the marketed once-daily LABAs indacaterol, olodaterol and vilanterol. Abediterol was the compound with the highest in vitro potency for dog, guinea pig and human ß2-adrenoceptors. In electrical field stimulated guinea pig trachea, abediterol demonstrated 5-, 44- and 77-fold greater potency than olodaterol, indacaterol and vilanterol, respectively. In anaesthetised guinea pigs, inhaled abediterol was also the most potent compound, with 5-20 times higher bronchoprotective potency than other once-daily LABAs against acetylcholine. The bronchoprotective half-life of abediterol in guinea pigs was 36h compared with 51h for indacaterol, 47h for olodaterol, and 18h for vilanterol. In anaesthetised dogs, abediterol also inhibited acetylcholine-induced bronchoconstriction, with higher potency than olodaterol and vilanterol [ID40 (dose inhibiting bronchoconstriction by 40%) of 0.059µg/kg, 0.180µg/kg and 2.870µg/kg, respectively]. In parallel, effects on heart rate in dogs were also measured. Abediterol showed greater safety index (defined as the ratio of the maximal dose without effect on heart rate and the ID40) than olodaterol and vilanterol (10.5 versus 4.9 and 2.4, respectively). Taken together, these data suggest that abediterol offers potent bronchodilation and a sustained duration of action suited to once-daily dosing, plus a reduced potential for class-related cardiac side effects.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Benzoxazinas/farmacologia , Álcoois Benzílicos/farmacologia , Clorobenzenos/farmacologia , Indanos/farmacologia , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Animais , Cães , Cobaias , Masculino , Quinolonas/efeitos adversos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Fatores de TempoRESUMO
This study characterised the in vitro and in vivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide and glycopyrronium bromide, using tiotropium bromide and ipratropium bromide as comparators. All four antagonists had high affinity for the five muscarinic receptor sub-types (M1-M5); aclidinium had comparable affinity to tiotropium but higher affinity than glycopyrronium and ipratropium for all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors than aclidinium and tiotropium but more slowly than ipratropium; all four compounds dissociated more rapidly from M2 receptors than from M3 receptors. In vitro, aclidinium, glycopyrronium and tiotropium had a long duration of action at native M3 receptors (>8 h versus 42 min for ipratropium). In vivo, all compounds were equi-potent at reversing acetylcholine-induced bronchoconstriction. Aclidinium, glycopyrronium and ipratropium had a faster onset of bronchodilator action than tiotropium. Aclidinium had a longer duration of action than glycopyronnium (time to 50% recovery of effect [t½ offset] = 29 h and 13 h, respectively); these compare with a t½ offset of 64 h and 8 h for tiotropium and ipratropium, respectively. Aclidinium was less potent than glycopyrronium and tiotropium at inhibiting salivation in conscious rats (dose required to produce half-maximal effect [ED50] = 38, 0.74 and 0.88 µg/kg, respectively) and was more rapidly hydrolysed in rat, guinea pig and human plasma compared with glycopyrronium or tiotropium. These results indicate that while aclidinium and glycopyrronium are both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2, aclidinium has a longer dissociation half-life at M3 receptors and a longer duration of bronchodilator action in vivo than glycopyrronium. The rapid plasma hydrolysis of aclidinium, coupled to its kinetic selectivity, may confer a reduced propensity for systemic anticholinergic side effects with aclidinium versus glycopyrronium and tiotropium.
Assuntos
Broncodilatadores/farmacologia , Glicopirrolato/farmacologia , Antagonistas Muscarínicos/farmacologia , Tropanos/farmacologia , Acetilcolina/farmacologia , Animais , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacocinética , Glicopirrolato/efeitos adversos , Glicopirrolato/farmacocinética , Cobaias , Meia-Vida , Humanos , Hidrólise , Ipratrópio/efeitos adversos , Ipratrópio/farmacocinética , Ipratrópio/farmacologia , Masculino , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacocinética , Ratos , Ratos Wistar , Derivados da Escopolamina/efeitos adversos , Derivados da Escopolamina/farmacocinética , Derivados da Escopolamina/farmacologia , Especificidade da Espécie , Fatores de Tempo , Brometo de Tiotrópio , Tropanos/efeitos adversos , Tropanos/farmacocinéticaRESUMO
Abediterol is a novel potent, long-acting inhaled ß(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human ß(2)-adrenoceptor and a functional selectivity over ß(1)-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human ß(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC(50) = 1.9 ± 0.4 nM; t½ onset = 7-10 min) is not significantly different from that of formoterol, but its duration of action (t½ â¼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t½ = 36 h) than salmeterol (t½ = 6 h) and formoterol (t½ = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Albuterol/análogos & derivados , Albuterol/farmacologia , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Broncoconstrição/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Etanolaminas/farmacologia , Fumarato de Formoterol , Cobaias , Humanos , Masculino , Monócitos/efeitos dos fármacos , Monócitos/patologia , Quinolonas/farmacologia , Xinafoato de SalmeterolRESUMO
The synthesis of diverse functionalized ureas in a semi-parallel fashion is described, as well as their ß(1)/ß(2)-adrenergic activities and the corresponding structure-activity relationship (SAR). We have focused on lipophilicity and duration of action, and we have discovered a strong correlation in this series of molecules. A quantitative structure-activity relationship (QSAR) analysis will be presented that quantifies this relationship.
Assuntos
Descoberta de Drogas , Fenol/síntese química , Ureia/síntese química , Agonistas de Receptores Adrenérgicos beta 2 , Estrutura Molecular , Fenol/química , Fenol/farmacologia , Relação Quantitativa Estrutura-Atividade , Ureia/química , Ureia/farmacologiaRESUMO
Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)). [(3)H]Aclidinium dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(3)H]aclidinium at the M(2) receptor was shorter than at the M(3) receptor, demonstrating kinetic selectivity for the M(3) receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.