Steroidal C-21 mercapto derivatives as dissociated steroids: Discovery of an inhaled dissociated steroid

Biju, Purakkattle; McCormick, Kevin D.; Aslanian, Robert; Berlin, Michael; Solomon, Daniel H.; Chapman, Richard W.; McLeod, Robbie L.; Prelusky, Daniel; Eckel, Stephen; Kelly, George; Natiello, Michelle; House, Aileen; Fernandez, Xiomara; Bitar, Rema; Phillips, Jonathan E.; Anthes, John C.

doi:10.1016/j.bmcl.2011.08.108

Cited by 17 publications

(8 citation statements)

References 33 publications

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“…Synthesis of MS4 and MS6 -Two previously reported, yet not fully characterized, thiobenzothiazole-modified hydrocortisone analogues (MS4 and MS6) were synthesized via slight modifications of known methods (26). The complete synthetic procedures and chemical characterizations for both molecules are provided in supplemental Fig.…”

Section: Methodsmentioning

confidence: 99%

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Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Burke

May

Noland³

et al. 2015

Journal of Biological Chemistry

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Background: Glucocorticoids impair islet ␤-cell function via glucocorticoid receptor (GR) activation. Results: Thiobenzothiazole-modified hydrocortisone compounds exhibit anti-inflammatory properties with reduced impact on insulin secretion. Conclusion: Novel glucocorticoids can be engineered to reduce impact on ␤-cell mass and function. Significance: Improved GR agonists will be beneficial in a variety of clinical settings.

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Section: Methodsmentioning

confidence: 99%

“…Thiobenzathiazole modifications to the hydrocortisone backbone were reported to create compounds with dissociated activity (i.e. separation of transactivation from transrepression) (26). However, whether such molecules demonstrate improved therapeutic index (e.g.…”

Section: Ms4 Has An Improved Metabolic Profile When Compared Withmentioning

confidence: 99%

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Burke

May

Noland³

et al. 2015

Journal of Biological Chemistry

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“…(29)(30)(31)(32) Uniform lung distribution is possible as a high quality respirable aerosol is generated and maintained for a period long enough to allow the mice to inhale an efficacious deposited dose. (20) The deposited dose can be utilized to calculate a therapeutic index, (33) ensuring that the drug has an appropriate exposure multiple (usually >10) present to rule out the manifestation of any systemic side effects and is also useful when planning inhaled toxicology studies.…”

Section: Discussionmentioning

confidence: 99%

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

Phillips

Renteria

Burns

et al. 2016

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion. Methods: This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response. Results: RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC 50 of 2.5 -0.7 nM and PGD 2 production from mast cells with an IC 50 of 8.3 -1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC 50 (RN983) ¼ 59 lg/kg) than the bagonist salbutamol (IC 50 (salbutamol) ¼ 15 lg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC 50 (RN983) ¼ <3 lg/kg) than the inhaled corticosteroid budesonide (IC 50 (budesonide) ¼ 27 lg/kg) in the mouse model of the LAR. Conclusions: Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and b-agonists in severe asthmatics due to its potent inhibition of mast cell activation.

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“…In an effort for the discovery and development of dissociated glucocorticoids for the treatment of various inflammatory diseases, C-21 MBTs 28 (Figure13) were prepared [99] by the treatment of hydrocortisone mesylate with MBT in acetone. A compound possessing furan-2-carboxylate group at seventeenth position of the steroidal nucleus ( 28 R = H and R 1 = CO-2-furyl) showed a significant dissociated profile in in vitro functional assays, but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis), while maintaining efficacy against pulmonary inflammation and lung function.…”

Section: Biologically Active 2-mercaptobenzothiazolesmentioning

confidence: 99%

Biological Activities of 2-Mercaptobenzothiazole Derivatives: A Review

Azam¹

2012

Sci. Pharm.

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2-Mercaptobenzothiazoles are an important class of bioactive and industrially important organic compounds. These compounds are reported for their antimicrobial and antifungal activities, and are subsequently highlighted as a potent mechanism-based inhibitor of several enzymes like acyl coenzyme A cholesterol acyltransferase, monoamine oxidase, heat shock protein 90, cathepsin D, and c-Jun N-terminal kinases. These derivatives are also known to possess antitubercular, anti-inflammatory, antitumor, amoebic, antiparkinsonian, anthelmintic, antihypertensive, antihyperlipidemic, antiulcer, chemoprotective, and selective CCR3 receptor antagonist activity. This present review article focuses on the pharmacological profile of 2-mercaptobenzothiazoles with their potential activities.

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Steroidal C-21 mercapto derivatives as dissociated steroids: Discovery of an inhaled dissociated steroid

Cited by 17 publications

References 33 publications

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

Biological Activities of 2-Mercaptobenzothiazole Derivatives: A Review

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