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.

Crystal structure of tert-butyl (phenylsulfinyl)carbamate, C11H15NO3S

“…Sulfonimidamide is an isostere of sulphonamide, which is formed by replacing one of the O-atoms by nitrogen of sulfonamide. The title compound can be considered as a potential pecursor for the preparation of sulfonimidamids [9][10][11][12]. However crystal structures of sulfinylcarbamate derivatives are rare.…”

One‐Pot, Three‐Component Sulfonimidamide Synthesis Exploiting the Sulfinylamine Reagent N‐Sulfinyltritylamine, TrNSO

“…[1] Like their congeners,t hey are chemically and metabolically stable, [2] but in addition, the substitution of an oxygen atom for an itrogen leads to astereogenic sulfur center,presents further opportunities for directed hydrogen bonding,a nd provides an additional site for functionalization. These properties present unique opportunities for medicinal chemists and agrochemists,a nd they have been reported as carboxylic acid [3] and sulfonamide bioisosteres, [4] and their use as BACE inhibitors [5] and kinase inhibitors [6] has been disclosed in recent patents.T heir use in medicinal-and agrochemistry has recently been the subject of ar eview by Arvidsson and co-authors,w here it is noted that "since 2012, there have been more patents and publications on compounds with as ulfonimidamide moiety than collectively over history,demonstrating that this functional group is gaining momentum". [1] In order to capitalize on this momentum and the increasing awareness of sulfonimidamides,more convenient and efficient methods for their preparation are required;u nlike sulfonamides,t here has been little progress in this regard.…”

Institutional Profile: the National Swedish Academic Drug Discovery & Development Platform at Scilifelab

“…The focus for the ADME of therapeutics (ADMEoT) facility is to determine absorption, distribution, metabolism and excretion (ADME), and perform pharmaceutical profiling of small molecule compounds and antibodies [20–23]. The ADMEoT facility services include giving access to expertise and know-how to the project teams with regard to identifying critical points for drug discovery, study planning, performing wet lab studies and support to principal investigator in ADME/PK questions in the project and in discussions with potential investors and regulatory bodies.…”