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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Australian researchers explore new asthma treatments in world-first trials – International Business Times AU


International Business Times AU

Australian researchers explore new asthma treatments in world-first trials
International Business Times AU
In a world-first human trial, Australian researchers will test a vaccine used to combat childhood bacterial infections to treat a common type of asthma. The Hunter Medical Research Institute will study if an injection called Prevenar 13, which is given

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Australian researchers explore new treatments for asthma in world-first trials – International Business Times AU


International Business Times AU

Australian researchers explore new treatments for asthma in world-first trials
International Business Times AU
In a world-first human trial, Australian researchers will test a vaccine used to combat childhood bacterial infections to treat a common type of asthma. Hunter Medical Research Institute will study if an injection called Prevenar 13, which is given to

View full post on asthma – Google News

Study compares combination treatments for African-American adults with asthma – Pharmacy Today, American Pharmacists Association, pharmacist.com


JAMA: The Journal of the American Medical Association

Study compares combination treatments for African-American adults with asthma
Pharmacy Today, American Pharmacists Association, pharmacist.com
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Study compares combination treatments for black adults with asthma The JAMA … – EurekAlert (press release)


Medical Xpress

Study compares combination treatments for black adults with asthma The JAMA
EurekAlert (press release)
Among black adults with asthma treated with an inhaled corticosteroid, adding a long-acting beta-agonist did not improve the time to an asthma exacerbation compared with adding the anticholinergic tiotropium, according to a study in the October 27
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Study compares combination treatments for black adults with asthma – Medical Xpress


Medical Xpress

Study compares combination treatments for black adults with asthma
Medical Xpress
Among black adults with asthma treated with an inhaled corticosteroid, adding a long-acting beta-agonist did not improve the time to an asthma exacerbation compared with adding the anticholinergic tiotropium, according to a study in the October 27

View full post on asthma – Google News

Major European study moves a step closer to treatments for severe asthma – EurekAlert (press release)

Major European study moves a step closer to treatments for severe asthma
EurekAlert (press release)
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