Optimization of substituted imidazobenzodiazepines as novel asthma treatments.

Optimization of substituted imidazobenzodiazepines as novel asthma treatments.

Eur J Med Chem. 2016 Nov 24;126:550-560

Authors: Jahan R, Stephen MR, Forkuo GS, Kodali R, Guthrie ML, Nieman AN, Yuan NY, Zahn NM, Poe MM, Li G, Yu OB, Yocum GT, Emala CW, Stafford DC, Cook JM, Arnold LA

Abstract
We describe the synthesis of analogs of XHE-III-74, a selective ?4?3?2 GABAAR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place of methoxy group at C-8 position was evaluated for isotope effects in preclinical assays; including microsomal stability, cytotoxicity, and sensorimotor impairment. The deuterated compounds were equally or more metabolically stable than the corresponding non-deuterated analogs and increased sensorimotor impairment was observed for some deuterated compounds. Thioesters were more cytotoxic in comparison to other carboxylic acid derivatives of this compound series. The most promising compound 16 identified from the in vitro screens also strongly inhibited smooth muscle constriction in ex vivo guinea pig tracheal rings. Smooth muscle relaxation, determined by reduction of airway hyperresponsiveness with a murine ovalbumin sensitized and challenged model, showed that 16 was efficacious at low methacholine concentrations. However, this effect was limited due to suboptimal pharmacokinetics of 16. Based on these findings, further analogs of XHE-III-74 will be investigated to improve in vivo metabolic stability while retaining the efficacy at lung tissues involved in asthma pathology.

PMID: 27915170 [PubMed – as supplied by publisher]

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Evaluation of Novel Lung Function Parameters and Quantitative Computed Tomography (qCT) in Patients With Pulmonary Disease

Conditions:   Chronic Obstructive Pulmonary Disease;   Bronchial Asthma;   Interstitial Lung Disease
Interventions:   Device: multiple breath washout test (MBW);   Device: impulse oscillometry (IOS);   Device: body plethysmography (BP);   Device: quantitative computed tomography (qCT)
Sponsor:   Universitätsmedizin Mannheim
Recruiting – verified July 2016

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LINX®, a Novel Treatment for Patients With Refractory Asthma Complicated by Gastroesophageal Reflux Disease – Medscape

LINX®, a Novel Treatment for Patients With Refractory Asthma Complicated by Gastroesophageal Reflux Disease
Medscape
Background: Gastroesophageal reflux disease is one of the most common comorbidities in patients with asthma. Gastroesophageal reflux disease can be linked to difficult-to-control asthma. Current management includes gastric acid suppression therapy and …

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Novel gene therapy shows potential for lung repair in asthma American Thoracic Society – EurekAlert (press release)


EurekAlert (press release)

Novel gene therapy shows potential for lung repair in asthma American Thoracic Society
EurekAlert (press release)
ATS 2016, SAN FRANCISCO — A new study has demonstrated a way to deliver a nanoparticle-based gene therapy, in order to repair lungs damaged by chronic allergic asthma and to reduce inflammation that causes asthma attacks. The potential therapy …

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Novel genetic method could lead to vaccine for cancer, asthma – Times of India


The Siasat Daily

Novel genetic method could lead to vaccine for cancer, asthma
Times of India
Danish researchers have developed a novel genetic method that could lead to the development of safe and effective vaccines for controlling diseases such as cancer, asthma, and allergies. "The major research breakthrough is that we have created a
Novel technique to develop vaccines for cancer, asthma: studyThe Siasat Daily

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