Sulfoximines from a Medicinal Chemist's Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery.
Sulfoximines, sulfondiimides and sulfonimidamides are fascinating but not yet fully explored variants of the common sulfone or sulfonamide motif. In this study, we report the physicochemical and in vitro properties of sulfoximines and compare them with related analogs and isosteres. Furthermore, we present a matched molecular pair analysis of compounds from drug discovery projects within Boehringer Ingelheim. We demonstrate that the sulfoximine moiety is a chemically stable, comparatively polar and weakly basic functional group, often leading to favorable aqueous solubility, permeability and metabolic stability. Moreover, their additional vectors at nitrogen enable simple chemical modifications and thus facilitate exploration and fine-tuning of the molecular properties. We conclude that sulfoximines and their congeners do not exhibit any intrinsic flaw but significantly enrich the toolbox of medicinal chemists.
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.
Marcus
M
Frings
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.
Carsten
C
Bolm
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany.
Andreas
A
Blum
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany. Electronic address: christian.gnamm@boehringer-ingelheim.com.
Christian
C
Gnamm
D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D013457:Sulfur Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D013457:Sulfur Compounds
Metabolic stability; Permeability; Solubility; Sulfondiimides; Sulfonimidamides; Sulfoximines; Synthesis