Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P1 agonists

Buzard, Daniel J.; Han, Sangdon; Thoresen, Lars; Moody, Jeanne; Lopez, Luis; Kawasaki, Andrew M.; Schrader, Thomas O.; Sage, Carleton R.; Gao, Yinghong; Edwards, Jeff; Barden, Jeremy; Thatte, Jayant; Fu, Li; Solomon, Michelle; Liu, Ling; Al-Shamma, Hussien; Gatlin, Joel; Le, Minh; Xing, Charles; Espinola, Sheryll; Jones, Robert M.

doi:10.1016/j.bmcl.2011.05.110

Cited by 10 publications

(8 citation statements)

References 10 publications

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“…In 38, an early member of the series that ultimately led to the polar-acidic clinical compound etrasimod (Figure 8; 58), the pendant carboxylic acid is attached to an indoline that serves as the central aromatic system. 46 Additional clinical or near-clinical compounds of this category are 64, 67, and 68 (Figures 8 and 9). Polar-Basic.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P₁) Agonists and Future Perspectives

Dyckman

2017

J. Med. Chem.

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The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P). The diverse structural classes of S1P agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify next-generation S1P agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P are touched upon.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P₁) Agonists and Future Perspectives

Dyckman

2017

J. Med. Chem.

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“…The trends in all these studies suggest that anionic headgroups with charges delocalized over three atoms are better able to activate all S1P receptors than anionic headgroups with reduced overall charge, or charge shared only by two atoms as in the carboxylate headgroup. Highly delocalized negative charge is not an absolute requirement, however, as highly potent non-lipid molecules with carboxylate headgroups [11–18] as well as uncharged trifluoromethyl [19,20] and other headgroups [21–25] combined with a variety of aromatic and heteroaromatic linker/tail combinations have been reported. The headgroup pocket also seems to be limited in size, as the sulfur atom in the thiophosphate is substantially larger than the corresponding oxygen atomin a phosphate group.…”

Section: Introductionmentioning

confidence: 99%

“…These data suggest that S1P 1 can also accommodate mildly bent shapes, but that S1P 2 and S1P 4 prefer more linear ligand geometries. The ability of S1P 3 to recognize both bent and linear shapes demonstrates why achieving S1P 1 -selective agonists that lack the bradycardia side effect mediated by S1P 3 action has been achieved by large jumps in structural space from the flexible phospholipid agonist analogs of S1P [11,13,17–19,21,22,25,36,41,42]. …”

Section: Introductionmentioning

confidence: 99%

Integrating the puzzle pieces: The current atomistic picture of phospholipid–G protein coupled receptor interactions

Parrill

Tigyi

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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A compelling question of how phospholipids interact with their target receptors has been of interest since the first receptor-mediated effects were reported. The recent report of a crystal structure for the S1P1 receptor in complex with an antagonist phospholipid provides interesting perspective on the insights that had previously been gained through structure–activity studies of the phospholipids, as well as modeling and mutagenesis studies of the receptors. This review integrates these varied lines of investigation in the context of their various contributions to our current understanding of phospholipid–receptor interactions. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

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“…20,21 Despite discovery of several potent and selective analogues, we failed to identify a compound with good activity in the mouse lymphocyte lowering (LL) experiment at an acceptable plasma concentration (e.g., 3 LL IC 50 = 1.62 μM). Furthermore, 3 was undetectable in rat brain and CSF after 24 h intravenous infusion.…”

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confidence: 99%

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

Buzard

Kim

Lopez

et al. 2014

ACS Med. Chem. Lett.

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APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P 1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P 1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

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Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P1 agonists

Cited by 10 publications

References 10 publications

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P₁) Agonists and Future Perspectives

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P₁) Agonists and Future Perspectives

Integrating the puzzle pieces: The current atomistic picture of phospholipid–G protein coupled receptor interactions

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

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Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P1 agonists

Cited by 10 publications

References 10 publications

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P1) Agonists and Future Perspectives

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P1) Agonists and Future Perspectives

Integrating the puzzle pieces: The current atomistic picture of phospholipid–G protein coupled receptor interactions

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor

Contact Info

Product

Resources

About

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P₁) Agonists and Future Perspectives

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P₁) Agonists and Future Perspectives