Etrasimod

• APD334
• C₂₆H₂₆F₃NO₃
• 457.493

1206123-37-6
2-[(3R)-7-{[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy}-1H,2H,3H,4H-cyclopenta[b]indol-3-yl]acetic acid

Name: Etrasimod arginine
CAS#: 1206123-97-8 (arginine)
Chemical Formula: C32H40F3N5O5
Exact Mass: 631.30
Molecular Weight: 631.700

FDA APPROVED, To treat moderately to severely active ulcerative colitis in adults,

Etrasimod, sold under the brand name Velsipity, is a medication that is used for the treatment of ulcerative colitis (UC).^[1] It is a selective sphingosine-1-phosphate (S1P) receptor modulator that modifies the activity of the immune system.^[1] It is taken by mouth.^[1]

Etrasimod was discovered by Arena Pharmaceuticals, with subsequent development by Pfizer.^[2]

Etrasimod is a synthetic next-generation selective Sphingosine 1-phosphate (S1P) receptor modulator that targets the S1P_1,4,5 with no detectable activity on S1P₂ and S1P₃ receptors. S1P receptors are membrane-derived lysophospholipid signaling molecules that are involved in the sequestration of circulating peripheral lymphocytes in lymph nodes.¹ Therefore, S1P receptor modulators like etrasimod were investigated in treating immune-mediated diseases like ulcerative colitis where a high level of inflammatory T cells is present in the gastrointestinal tract, thus causing diffuse mucosal inflammation.¹ In fact, it has been observed that antigen-activated T cells within peripheral lymphoid organs can transiently downregulate S1P receptor levels to facilitate immune cells trafficking into the intestinal mucosa.²

Etrasimod was approved on October 13, 2023, by the FDA under the brand name VELSIPITY for the treatment of adults with moderately to severely active ulcerative colitis. This approval was based on favorable results obtained from Pfizer’s Elevate UC Phase III registrational program, consisting of the Elevate UC 52 and Elevate UC 12 clinical trials, that investigates the efficacy of a 2-mg daily dose regimen of etrasimod, with a 32% and 26% remission rate observed in UC 52 and UC 12 trials respectively.⁴

Medical uses

Etrasimod is used for the treatment of moderate to severe ulcerative colitis.^[1]

Mechanism of action

It works by causing T cells to become trapped in the lymph nodes, preventing them from entering the bloodstream, from where they would travel to other tissues in the body and mediate inflammation.^{[3][4][5][6][7][8]}

Society and culture

Legal status

Velsipity was approved by the US Food and Drug Administration (FDA) in October 2023.^[1][9][10]

Names

Etrasimod is the international nonproprietary name.^[11]

SYN

ACS Med. Chem. Lett.2014, 5, 12, 1313–1317

Publication Date:November 4, 2014

https://doi.org/10.1021/ml500389m

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P₁ receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P₁ 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.

APD334 is the second eluting enantiomer (most retained) with a retention time of 48.4 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54-1.75 (m, 4H), 1.79-1.92 (m, 2H), 1.95-2.16 (m, 3H), 2.39 (dd, J = 16.0, 8.8 Hz, 1H), 2.61-2.83 (m, 4H), 3.23-3.34 (m, 1H), 3.45-3.56 (m, 1H), 5.14 (s, 2H), 6.74 (dd, J = 8.7, 2.4 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 10.50 (s, 1H), 12.24 (bs, 1H). 13C APT NMR (100 MHz, DMSO-d6): δ up (C, CH2): 23.1, 25.5, 35.5, 35.6, 68.6, 117.0, 124.7 (q, J = 273 Hz), 124.2, 126.8 (q, J = 28 Hz), 128.7, 136.1, 136.2, 144.6, 147.0, 151.9, 173.4; down (CH, CH3): 35.0, 40.5, 102.1, 110.0, 112.4, 124.1 (q, J = 5.7 Hz), 128.4, 131.7. 19F NMR (400 MHz, DMSO-d6) δ ppm -57.4. LCMS (ESI+): calcd for C26H27F3NO3+ [M+H] 458.19; found, 458.4. HRMS (ESI-): calcd for C26H25F3NO3- [M-H] 456.1792; found, 456.1776.

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References

1. ^ Jump up to:^{a b c d e f} Pfizer (12 October 2023). “Velsipity (etrasimod) tablets, for oral use” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 18 October 2023.
2. ^ Bayer M (2 May 2023). “Pfizer tosses newly acquired meds out of the Arena”. Fierce Biotech. Retrieved 13 October 2023.
3. ^ Atreya R, Neurath MF (April 2023). “The sphingosine-1-phosphate receptor agonist etrasimod in ulcerative colitis”. Lancet. 401 (10383): 1132–1133. doi:10.1016/S0140-6736(23)00228-3. PMID 36871570.
4. ^ Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, et al. (April 2023). “Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies”. Lancet. 401 (10383): 1159–1171. doi:10.1016/S0140-6736(23)00061-2. PMID 36871574.
5. ^ Dal Buono A, Gabbiadini R, Alfarone L, Solitano V, Repici A, Vetrano S, et al. (July 2022). “Sphingosine 1-Phosphate Modulation in Inflammatory Bowel Diseases: Keeping Lymphocytes Out of the Intestine”. Biomedicines. 10 (7). doi:10.3390/biomedicines10071735. PMC 9313037. PMID 35885040.
6. ^ Argollo M, Furfaro F, Gilardi D, Roda G, Allocca M, Peyrin-Biroulet L, et al. (April 2020). “Modulation of sphingosine-1-phosphate in ulcerative colitis”. Expert Opin Biol Ther. 20 (4): 413–420. doi:10.1080/14712598.2020.1732919. PMID 32093531.
7. ^ Al-Shamma H, Lehmann-Bruinsma K, Carroll C, Solomon M, Komori HK, Peyrin-Biroulet L, et al. (June 2019). “The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis”. J Pharmacol Exp Ther. 369 (3): 311–317. doi:10.1124/jpet.118.254268. PMID 30872391.
8. ^ Peyrin-Biroulet L, Christopher R, Behan D, Lassen C (May 2017). “Modulation of sphingosine-1-phosphate in inflammatory bowel disease”. Autoimmun Rev. 16 (5): 495–503. doi:10.1016/j.autrev.2017.03.007. PMID 28279838.
9. ^ Brooks M (13 October 2023). “FDA Approves New Drug for Ulcerative Colitis”. Medscape. Retrieved 13 October 2023.
10. ^ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216956Orig1s000ltr.pdf
11. ^ World Health Organization (2017). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 78”. WHO Drug Information. 31 (3). hdl:10665/330961.

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