RESUMO
A series of potent, selective and long-acting quinoline-based sulfonamide human H1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine.
Assuntos
Antagonistas dos Receptores Histamínicos H1/química , Quinolinas/química , Receptores Histamínicos H1/metabolismo , Rinite Alérgica/tratamento farmacológico , Sulfanilamidas/química , Sulfonamidas/química , Sulfonas/química , Administração Intranasal , Animais , Encéfalo/metabolismo , Cães , Cobaias , Meia-Vida , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Concentração Inibidora 50 , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Ratos , Receptores Histamínicos H1/química , Rinite Alérgica/metabolismo , Rinite Alérgica/patologia , Relação Estrutura-Atividade , Sulfanilamida , Sulfanilamidas/farmacocinética , Sulfanilamidas/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Sulfonas/farmacocinética , Sulfonas/uso terapêuticoRESUMO
The synthesis of potent amide-containing phthalazinone H1 histamine receptor antagonists is described. Three analogues 3e, 3g, and 9g were equipotent with azelastine and were longer-acting in vitro. Amide 3g had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day.
RESUMO
A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.