- Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach
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Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.
- Liu, Qingjie,Batt, Douglas G.,Weigelt, Carolyn A.,Yip, Shiuhang,Wu, Dauh-Rurng,Ruzanov, Max,Sack, John S.,Wang, Jinhong,Yarde, Melissa,Li, Sha,Shuster, David J.,Xie, Jenny H.,Sherry, Tara,Obermeier, Mary T.,Fura, Aberra,Stefanski, Kevin,Cornelius, Georgia,Khandelwal, Purnima,Tino, Joseph A.,Macor, John E.,Salter-Cid, Luisa,Denton, Rex,Zhao, Qihong,Dhar, T. G. Murali
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supporting information
p. 2510 - 2518
(2020/12/03)
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- TRICYCLIC SULFONES AS ROR GAMMA MODULATORS
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There are described RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.
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Paragraph 0406-0407
(2018/05/24)
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- HETEROCYCLIC SULFONES AS ROR GAMMA MODULATORS
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There are described RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ Gamma activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ Gamma activity, for example, autoimmune and/or inflammatory disorders.
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Page/Page column 87; 88
(2018/04/27)
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- Electrophilic fluorination of pyroglutamic acid derivatives: Application of substrate-dependent reactivity and diastereoselectivity to the synthesis of optically active 4-fluoroglutamic acids
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Electrophilic fluorination of enantiomerically pure 2-pyrrolidinones (4) derived from (L)-glutamic acid has been investigated as a method for the synthesis of single stereoisomers of 4-fluorinated glutamic acids. Reaction of the lactam enolate derived from 9 with NFSi results in a completely diastereoselective monofluorination reaction to yield the monocyclic trans-substituted α-fluoro lactam product 21. Unfortunately, a decreased kinetic acidity in 21 and other structurally related monofluorinated products renders them resistant to a second fluorination. In contrast, the bicyclic lactam 12 is readily difluorinated under the standard conditions described to yield the α,α-difluoro lactam 24. The difference in reactivity between the two types of related lactams is attributed mainly to the presence or lack of a steric interaction between the base used for deprotonation and the protecting group present in the pyrrolidinone substrates. This conclusion was reached based on analysis of the X-ray crystal structure of 21, molecular modeling, and experimental evidence. The key intermediates 21 and 24 are converted to (2S,4R)-4-fluoroglutamic acid and (2S)-4,4-difluoroglutamic acid, respectively.
- Konas,Coward
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p. 8831 - 8842
(2007/10/03)
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