title: Preclinical characterization of acyl sulfonimidamides: potential carboxylic acid bioisosteres with tunable properties.
abstract: Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pKa , 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.
authors: Department of Medicinal Chemistry, Division of Organic Pharmaceutical Chemistry, Biomedical Center, Uppsala University, P.O. Box 574, 751 23 Uppsala (Sweden).
authors: Sanjay R
authors: SR
authors: Borhade
authors: Richard
authors: R
authors: Svensson
authors: Peter
authors: P
authors: Brandt
authors: Per
authors: P
authors: Artursson
authors: Per I
authors: PI
authors: Arvidsson
authors: Anja
authors: A
authors: Sandström
mesh_terms: D000215:Acylation; D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000378:metabolism*; D002463:Cell Membrane Permeability; D055808:Drug Discovery; D006801:Humans; D011485:Protein Binding; D013457:Sulfur Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000577:Amides; D002264:Carboxylic Acids; D013457:Sulfur Compounds
keywords: acidity; acyl sulfonimidamides; bioisosteres; lipophilicity; permeability