In:
The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 44.11-44.11
Abstract:
MIDD0301 is a new lead compound designed for the oral treatment of asthma. It was developed from previously described α5β3γ2 selective GABAA receptor (GABAAR) modulators. MIDD0301 showed significant relaxation of Substance P contracted guinea pig tracheal rings ex vivo at low micromolar concentrations. In vivo, MIDD0301 decreased airway hyperresponsiveness in asthmatic ovalbumin-sensitized and challenged mice after five day b.i.d. oral administration. MIDD0301 reduced eosinophil, macrophage, and CD4+T-lymphocyte cell counts in broncoalveolar lavage fluid without stimulating mucus hyperplasia. Pro-inflammatory cytokines (IL-17A, IL-4, TNFα) were decreased in the lung while the anti-inflammatory cytokine IL-10 remained unchanged. Pharmacokinetic studies showed MIDD0301 has a half-life of approximately 14 hours and negligible brain distribution. The lack of adverse CNS side effects was confirmed with rotarod studies. CD4+ T-lymphocytes isolated from ova s/c mice showed a dose dependent change in transmembrane current with GABA and MIDD0301, confirming that MIDD0301 is acting via GABAAR. Overall, MIDD0301 represents a novel, orally available, and safe alternative for the treatment of asthma through airway smooth muscle relaxation and attenuation of airway inflammation.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.200.Supp.44.11
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2018
detail.hit.zdb_id:
1475085-5
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