Development of GABA<sub>A</sub> Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

Forkuo, Gloria S.; Guthrie, Margaret L.; Yuan, Nina Y.; Nieman, Amanda N.; Kodali, Revathi; Jahan, Rajwana; Rajesh, Stephen Michael; Yocum, Gene T.; Treven, Marco; Li, Guanguan; Yu, Olivia B.; Hartzler, Benjamin D.; Zahn, Nicolas M; Ernst, Margot; Emala, Charles W.; Stafford, Douglas C.; Cook, James M.; Arnold, Leggy A.

doi:10.1021/acs.molpharmaceut.6b00159

Cited by 26 publications

(76 citation statements)

References 47 publications

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“…Similar rotarod data were published previously for 5 and 9 , showing that 5 weakly induced sensorimotor impairment whereas 9 did not, likely due to the inability of the acid to penetrate the blood brain barrier. [26] Compound 7 (XHE-III-74) induced sensorimotor impairment in rats at 15 mg/kg (unpublished results). Taken together, compounds in this series that are stable in the presence of human and mouse liver microsomes and exhibited neither cytotoxicity nor sensorimotor impairment are 6, 9a, 16, 16a , and 17a .…”

Section: Resultsmentioning

confidence: 90%

“…Thus, 16 is able to relax airway smooth muscle consistent with other analogs of XHE-III-74. [25, 26]…”

Section: Resultsmentioning

confidence: 99%

“…Control mice were sensitized with ovalbumin but challenged with saline. [26] Separate groups of ovalbumin (S/C) BALB/c mice received a single 40 mg/kg i.p. dose of 16 forty minutes before the measurement or twice daily 40 mg/kg of 16 i.p.…”

Section: Resultsmentioning

confidence: 99%

“…XHE-III-74 ( 7 ),[25] XHE-III-74EE ( 5 ),[30] and XHE-III-74A ( 9 ). [26] Only a few of the compounds described herein induced sensorimotor effects comparable to diazepam, however at concentrations that were eight times greater. At 40 mg/kg deuterated compounds in comparison to non-deuterated compounds are more likely to impair sensorimotor abilities.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, XHE-III-74 reduced airway resistance in a murine house dust mite model of asthma. The ethyl ester of XHE-III-74 reduced airway hyperresponsiveness in a murine ovalbumin sensitized and challenged (S/C) asthma model, whereas XHE-III-74A, the corresponding carboxylic acid, significantly reduced airway eosinophilia[26] and reduced IL-2 production following PMA/PHA activation of Jurkat cells. Furthermore, XHE-III-74A exhibited no CNS effects because its negative charge precluded brain penetration.…”

Section: Introductionmentioning

confidence: 99%

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Optimization of substituted imidazobenzodiazepines as novel asthma treatments

Jahan

Stephen

Forkuo

et al. 2017

European Journal of Medicinal Chemistry

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We describe the synthesis of analogs of XHE-III-74, a selective α4β3γ2 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 inhibits 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.

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Section: Resultsmentioning

confidence: 90%

“…Thus, 16 is able to relax airway smooth muscle consistent with other analogs of XHE-III-74. [25, 26]…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Optimization of substituted imidazobenzodiazepines as novel asthma treatments

Jahan

Stephen

Forkuo

et al. 2017

European Journal of Medicinal Chemistry

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Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer

Roni

Zahn

Yocum

et al. 2022

Drug Development Research

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MIDD0301 is being developed as an oral drug to relax airway smooth muscle (ASM) and reduce lung inflammation in asthma. We report a comparative study of MIDD0301 and its S isomer (MIDD0301S), and found that the compounds have equivalent affinity for γ-aminobutyric acid type A receptor (GABA A R) expressed in rat brain, with half maximal inhibitory concentration values of 25.1 and 26.3 nM for the S and R enantiomers, respectively. Both compounds relaxed substance P contracted ASM within 30 min and neither enantiomer revealed affinity to 48 receptors in an off-target screen. Both enantiomers reduced airway hyperresponsiveness (AHR) with nebulized and oral dosing in two mouse models of bronchoconstriction.In A/J mice, which are very sensitive to methacholine-induced bronchoconstriction, we observed reduction of AHR at 10.8 mg/kg MIDD0301 and 15 mg/kg MIDD0301S. Using oral administration, 100 mg/kg/day for 3 days of either enantiomer was sufficient to reduce AHR. In a model of severe airway inflammation induced by interferon-γ and lipopolysaccharide (LPS), we observed reduction of AHR at 7.2 mg/kg for both enantiomers using nebulized administration, and at 100 mg/kg for oral administration. MIDD0301 and MIDD0301S did not undergo Phase I metabolism. Glucuronidation was observed for both compounds, whereas only MIDD0301 formed the corresponding glucoside in the presence of kidney microsomes. Pharmacokinetic analysis identified glucuronides as the major metabolite with concentrations up to 20-fold more than the parent compound. MIDD0301 glucuronide and MIDD0301 taurine bind GABA A Rs, although 10-fold weaker than MIDD0301. In mouse blood, the taurine adduct was only observed for MIDD0301.Overall, both compounds exhibited similar receptor binding and pharmacodynamic properties with subtle differences in metabolism and greater oral availability and blood concentrations of MIDD0301S.

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Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABA_A receptors

Vasovic

Divović

Treven

et al. 2019

European Journal of Pain

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γ‐Aminobutyric acid type A (GABAA) receptors containing the α6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK‐I‐56‐1 at concentrations below 1 µM enhanced γ‐aminobutyric acid (GABA) currents at recombinant rat α6β3γ2, α6β3δ and α6β3 receptors, whereas it was inactive at most GABAA receptor subtypes containing other α subunits. DK‐I‐87‐1 at concentrations below 1 µM was inactive at α6‐containing receptors and only weakly modulated other GABAA receptors investigated. Both plasma and brain tissue kinetics of DK‐I‐56‐1 were relatively slow, with half‐lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10–300 nM throughout a 24‐hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK‐I‐56‐1 during 14 days after surgery or with DK‐I‐56‐1 or DK‐I‐87‐1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK‐I‐56‐1 but not DK‐I‐87‐1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK‐I‐56‐1 that positively modulates α6 GABAA receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.

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Development of GABA_A Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

Cited by 26 publications

References 47 publications

Optimization of substituted imidazobenzodiazepines as novel asthma treatments

Optimization of substituted imidazobenzodiazepines as novel asthma treatments

Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer

Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABA_A receptors

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Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

Cited by 26 publications

References 47 publications

Optimization of substituted imidazobenzodiazepines as novel asthma treatments

Optimization of substituted imidazobenzodiazepines as novel asthma treatments

Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer

Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABAA receptors

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Development of GABA_A Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABA_A receptors