Route scouting and optimization of a potent sulfoximine-based inverse agonist of RORγt

Lafitte, Guillaume; Parnet, Véronique; Pierre, Romain; Raffin, Catherine; Vatinel, Rodolphe; Musicki, Branislav; Tomas, Loïc; Bouix‐Peter, Claire; Ouvry, Gilles; Daver, S.; Arlabosse, Jean-Marie; Boiteau, Jean‐Guy; Gerfaud, Thibaud; Harris, Craig S.

doi:10.1016/j.tet.2018.08.043

Cited by 4 publications

(4 citation statements)

References 19 publications

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“…Sulfoximine 31 revealed robust results after topical application in a preclinical mouse model of psoriasis. A scale‐up route to deliver the first 100 g of RORγ inverse agonist 31 has been published, [45] suggesting that the compound has been evaluated for IND‐enabling studies.…”

Section: Bioisosteric Replacement Of Non‐sulfur‐based Functional Groupsmentioning

confidence: 99%

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

Lücking¹

2022

Chemistry A European J

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Extension of the medicinal chemistry toolbox is in the vital interest of drug designers. However, the diffusion of an innovation can be a lengthy process. 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 Review 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: Bioisosteric Replacement Of Non‐sulfur‐based Functional Groupsmentioning

confidence: 99%

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

Lücking¹

2022

Chemistry A European J

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“…Sulfoximine 31 revealed robust results after topical application in a preclinical mouse model of psoriasis. A scale-up route to deliver the first 100 g of ROR inverse agonist 31 has been published, [43] suggesting that the compound has been evaluated for IND-enabling studies.…”

Section: Ror Inverse Agonistsmentioning

confidence: 99%

“…[65b] Figure 18. Chemical structures of Nrf2 activators dimethyl fumarate (43), VSC2 (44) and CH-3 (45).…”

Section: Covalent Inhibitionmentioning

confidence: 99%

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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“…The another key intermediate, tricyclic amine (1,2,3,5,6,7-hexahydro- s -indacen-4-amine) ( 26 ), and its corresponding isocyanate 27 , was synthesized via reported protocol on multigram scale . The coupling of sulfinimide 25 with 4-isocyanato-1,2,3,5,6,7-hexahydro- s -indacene ( 27 ) provided sulfinylurea 28 in high yields, using modified reaction conditions reported by Toth et al Synthesis of N -substituted sulfoximines using alkylamines and cyanamide , are reported in the literature. However, there are no reports for the synthesis of N -cyano sulfoximineurea, albeit synthesis of sulfinylurea followed by chlorination/amination to afford N -alkyl sulfoximineurea are documented in literature .…”

mentioning

confidence: 99%

Discovery of N-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors

Agarwal

Sasane

Shah

et al. 2020

ACS Med. Chem. Lett.

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NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC 50 = 7 nM) and analogues were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1β secretion in mice.

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Route scouting and optimization of a potent sulfoximine-based inverse agonist of RORγt

Cited by 4 publications

References 19 publications

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

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

Discovery of N-Cyano-sulfoximineurea Derivatives as Potent and Orally Bioavailable NLRP3 Inflammasome Inhibitors

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