The Novartis Chemical Sciences Lecture: Michael Shultz & M. Christina White

M. Christina White

Chemical Tailoring at C—H Bonds

Michael Shultz

 Sulfoximines as secondary sulfonamide isosteres: Paradoxical improvements in solubility and plasma protein binding 

In recent years, sulfoximines have been recognized as underutilized functional groups in medicinal chemistry. Conversion of other common functional groups, such as a sulfone to primary sulfoximines, results in improved physicochemical properties which has been well documented. Secondary sulfonamides are often identified in hit generation and hit to lead campaigns, however there exists no literature describing the exploration of secondary sulfoximines as bioisosteric replacements.

During a recent hit generation campaign, a large number of secondary sulfonamides were identified and we were curious how replacing the sulfonamide with an endo-sulfoximine would alter the properties. While the predictions suggested this might be an undesirable isostere due to a higher clogP, the resulting secondary sulfoximines showed consistent, and paradoxical improvements in many properties. Despite having lower polarity (EPSA due to loss of HBD and HBA by replacing oxygen with carbon), secondary sulfoximines have consistently higher solubility, lower plasma protein binding (human serum albumin) without their permeability, CHI IAM or measured logD values differing significantly from the corresponding sulfonamide. Through an extensive matched molecular pair (MMP) analysis we found that the lower melting point of the sulfoximines likely increased both the water and octanol solubility, which is consistent with the paradoxical improvements in solubility. We further demonstrate that the reduction in HSA binding is likely due to the removal of the acidic NH of the sulfonamide and describe the differences in in silico, in vitro and in vivo ADME via this MMP analysis. Our understanding of hydrophobicity and lipophilicity was reconsidered based on these findings and the consequences of altering our thinking of theses terms will be discussed. Furthermore, the effects on conformation, with specific detail to bond lengths, bond angles and torsion angles will be presented to justify why replacements of sulfonamides prior to lead optimization is justified. Finally, we will show improved conditions for the synthesis of secondary sulfoximine libraries and our collaboration to make chiral sulfoximine building blocks readily available.

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