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Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.ORCID iD: 0000-0002-2885-2016
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2015 (English)In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 10, no 3, 455-460 p.Article in journal (Refereed) Published
Abstract [en]

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.

Place, publisher, year, edition, pages
2015. Vol. 10, no 3, 455-460 p.
Keyword [en]
acidity, acyl sulfonimidamides, bioisosteres, lipophilicity, permeability
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-248814DOI: 10.1002/cmdc.201402497ISI: 000350456200003PubMedID: 25630705OAI: oai:DiVA.org:uu-248814DiVA: diva2:801454
Available from: 2015-04-09 Created: 2015-04-08 Last updated: 2017-12-04Bibliographically approved

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Svensson, RichardBrandt, PeterArtursson, PerSandström, Anja

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