title: Optimization of substituted imidazobenzodiazepines as novel asthma treatments.
abstract: 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 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.
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Rajwana
authors.initials: R
authors.lastname: Jahan
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Michael Rajesh
authors.initials: MR
authors.lastname: Stephen
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Gloria S
authors.initials: GS
authors.lastname: Forkuo
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Revathi
authors.initials: R
authors.lastname: Kodali
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Guthrie
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Nieman
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Nina Y
authors.initials: NY
authors.lastname: Yuan
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Zahn
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Poe
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Guanguan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Olivia B
authors.initials: OB
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Columbia University, New York, NY, 10032, United States.
authors.forename: Gene T
authors.initials: GT
authors.lastname: Yocum
authors.affiliation: Department of Anesthesiology, Columbia University, New York, NY, 10032, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Stafford
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States. Electronic address: capncook@uwm.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, United States. Electronic address: arnold2@uwm.edu.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003251:Constriction, Pathologic / Q000188:drug therapy; D003903:Deuterium / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006168:Guinea Pigs; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D011963:Receptors, GABA-A / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000473:pathology
chemical_list: D011963:Receptors, GABA-A; D013463:Sulfuric Acid Esters; D016210:Methacholine Chloride; D001569:Benzodiazepines; D003903:Deuterium
keywords: Airway hyperresponsiveness; Airway smooth muscle; Asthma; Deuterated compounds; GABA(A) receptor; XHE-III-74