Sulfoximines as potent RORγ inverse agonists

Ouvry, Gilles; Bihl, Franck; Bouix‐Peter, Claire; Christin, Olivier; Defoin-Platel, Claire; Déret, Sophie; Feret, Christophe; Froude, David; Hacini‐Rachinel, Fériel; Harris, Craig S.; Hervouet, Catherine; Lafitte, Guillaume; Luzy, Anne-Pascale; Musicki, Branislav; Orfila, Danielle; Parnet, Véronique; Pascau, Coralie; Pierre, Romain; Raffin, Catherine; Rossio, Patricia; Spiesse, Delphine; Taquet, Nathalie; Thoreau, E.; Vatinel, Rodolphe; Vial, Emmanuel; Hennequin, Laurent

doi:10.1016/j.bmcl.2018.03.041

Cited by 17 publications

(18 citation statements)

References 25 publications

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“…However, rather than sulfoximines only being diminished to their now popular use as sulfonamide/sulfone bioisosteres with good stability and ADME properties and potentially promising IP, recent developments indicate that the versatile sulfoximine group offers many more opportunities to drug designers. ROR inverse agonist 31 [41] and PDE5 inhibitor 33 [8b] illustrate that it is also worthwhile considering sulfoximines for the replacement of non-sulfur-based functional groups such as alcohols and amines. Moreover, the utilization of all three exit vectors of the tetrahedral sulfoximine group via the structurally diverse options for N-functionalization offers access to novel chemical space.…”

Section: Discussionmentioning

confidence: 99%

“…Inverse agonist 30 (Figure 11) from GSK, which is characterized by a hydrophilic hydroxymethyl group, suggested that the ROR ligand binding domain can tolerate a certain amount of hydrophilicity in this region, and inspired a team at Nestlé Skin Health to screen polar structural alternatives at this position. [41] Based on the comparable pKa values, NH sulfoximines have been suggested as bioisosteres of alcohols. [42] Introduction of a sulfoximine group to the ROR lead series, exemplified by compound 31 (Figure 11), was indeed found to maintain good potency in a cellular in vitro assay [IC50 ROR: 17 nM (30) vs 26 nM (31)] but strongly reduced lipophilicity [logD pH 6.5: 5.9 (30) vs 4.6 (31)], resulting in significantly improved lipophilic efficiency [1.9 (30) vs 3.0 (31)].…”

Section: Ror Inverse Agonistsmentioning

confidence: 99%

“…TMTHSI was, for example, utilized successfully for the preparation of folic acid functionalized core cross-linked polymeric micellar nanoparticles (42, Figure 17). (40), TMTHSI (41) and folic acid functionalized core cross-linked polymeric micellar nanoparticles (42).…”

Section: Tmth-sulfoximine (Tmthsi) Click Reagentmentioning

confidence: 99%

“…Figure 17. Chemical structures of TMTH(40), TMTHSI(41) and folic acid functionalized core cross-linked polymeric micellar nanoparticles(42).…”

mentioning

confidence: 99%

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Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

Lücking¹

2022

Preprint

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Extension of the medicinal chemistry toolbox is in the vital interest of drug designers who are confronted with the task of finding molecular solutions for an ever-increasing biological target space. However, the diffusion of an innovation can be a lengthy process even within the drug discovery community which faces enormous pressure to formulate effective solutions for patients in a timely manner. Along these lines, it took almost 70 years before the use of the sulfoximine group reached a critical mass in medicinal chemistry. Even though interest in this versatile functional group has increased exponentially in recent years, there is ample room for further innovative applications. This minireview highlights emerging trends and opportunities for drug designers for the utilization of the sulfoximine group in medicinal chemistry, such as in the construction of complex molecules, proteolysis targeting chimeras (PROTACs), antibody–drug conjugates (ADCs) and novel warheads for covalent inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Ror Inverse Agonistsmentioning

confidence: 99%

Section: Tmth-sulfoximine (Tmthsi) Click Reagentmentioning

confidence: 99%

“…Figure 17. Chemical structures of TMTH(40), TMTHSI(41) and folic acid functionalized core cross-linked polymeric micellar nanoparticles(42).…”

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confidence: 99%

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Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

Lücking¹

2022

Preprint

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“…The resulting introduction of a sulfoximine led to an increased aqueous solubility while maintaining potency, which allowed for the advancement of 1 to the clinic where it is currently undergoing multiple phase II clinical trials. 9 Other discovery programs at Bayer, 4b-c, f, 10 Pfizer, 11 Genentech, 12 Hoffman-La Roche, 13 Novartis, 14 Nestlé Skin Health 15 and Corteva Agriscience, 16 have been actively researching neglected S(VI) functional groups with respect to methods for their installation and incorporation into lead scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Practical and Scalable Installation of Neglected S(VI) Functionality with Applications to the Enantiospecific Synthesis of Pharmaceuticals

Shultz¹,

Scattolin²,

Wojtas³

et al. 2021

Preprint

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<p>Sulfoximines and related sulfonimidoyl groups have been largely ignored for decades until their value was demonstrated in biological settings. The realization of their importance has ushered in a new wave of discovery and pharmaceutical applications. In attempts to remove the “neglected” description of the lesser-known S(VI) groups, a practical and modular approach for a-substituted heterocycles bearing sulfonimidoyl functional groups was developed. A variety of sulfoximines containing diverse functionality and complexity were rapidly introduced in an enantiospecific fashion with good to excellent yields. Pharmaceutically important heterocyclic scaffolds were shown to undergo the facile nucleophilic substitution, while sulfoximines, sulfonimidamides and sulfondiimines were all demonstrated to be compatible nucleophiles. The utility and practicality of the method was exhibited in target- and diversity-oriented syntheses of four sulfoximine-containing pharmaceuticals including ceralasertib, an ATR inhibitor currently in clinical trials. The introduction of underexplored sulfur functionality to common heterocyclic pharmacophores provides a practical platform for rapid analog development that is expected to aid future efforts in the discovery sciences.</p>

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Diversification of NH‐Aryl Sulfoximines through Iridium‐Catalyzed ortho‐ and meta‐Selective C−H Borylation

van Bonn,

Soerensen,

Schmitz

et al. 2023

Adv Synth Catal

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Sulfoximines as potent RORγ inverse agonists

Cited by 17 publications

References 25 publications

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

Practical and Scalable Installation of Neglected S(VI) Functionality with Applications to the Enantiospecific Synthesis of Pharmaceuticals

Diversification of NH‐Aryl Sulfoximines through Iridium‐Catalyzed ortho‐ and meta‐Selective C−H Borylation

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