Rovafovir etalafenamide
GS-9131
UNII-U8S0IC8DY7
ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate
L-Alanine, N-((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydro-2-furanyl)oxy)methyl)phenoxyphosphinyl)-, ethyl ester
CAS: 912809-27-9
Chemical Formula: C21H24FN6O6P
Molecular Weight: 506.43
- Originator Gilead Sciences
- Class Antiretrovirals; Purine nucleosides; Small molecules
- Mechanism of Action Nucleoside reverse transcriptase inhibitors
- Phase II HIV-1 infections
- 03 Apr 2018 Phase-II clinical trials in HIV-1 infections (Treatment-experienced) in Uganda (PO) (NCT03472326)
- 21 Mar 2018 Gilead Sciences plans a phase II study for HIV-1 infections in March 2018 (NCT03472326)
- 26 Mar 2009 Preclinical pharmacokinetics data in HIV-1 infections presented at the 237th American Chemical Society National Meeting (237th-ACS-2009)
Rovafovir Etalafenamide, also known as GS-9131, is an anti-HIV Nucleoside Phosphonate prodrug.
POSTER
http://www.croiconference.org/sites/default/files/posters-2017/436_White.pdf
Patent
WO 2006110157
WO 2008103949
WO 2010005986
PATENT
WO 2012159047
PATENT
WO-2019027920
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019027920&tab=PCTDESCRIPTION&maxRec=1000
As discussed in U.S. Pat. Nos. 7,871,991, 9,381,206, 8,951,986, and 8,658,617, ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate is a reverse transcriptase inhibitor that blocks the replication of HIV viruses, in vivo and in vitro, and has limited undesirable side effects when administered to human beings. This compound has a favorable in vitro resistance profile with activity against Nucleoside RT Inhibitor (NRTI)-Resistance Mutations, such as Ml 84V, K65R, L74V, and one or more (e.g., 1, 2, 3, or 4) TAMs (thymidine analogue mutations). It has the following formula (see, e.g., U.S. Pat. No. 7,871,991), which is referred to as Formula I:
[0004] Ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate is difficult to isolate, purify, store for an extended period, and formulate as a pharmaceutical composition.
[0005] The compound of formula la was previously identified as the most chemically stable form of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-
yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate. See, e.g. , U.S. Pat. Nos. 8,658,617,
8,951,986, and 9,381,206. However, a total degradation increase of 2.6% was observed when the compound of formula (la) was stored at 25 °C/60% RH over 6 months. Therefore, the compound of formula la requires refrigeration for long-term storage.
[0006] Accordingly, there is a need for stable forms of the compound of Formula I with suitable chemical and physical stability for the formulation, therapeutic use, manufacturing, and storage of the compound. New forms, moreover, can provide better stability for the active pharmaceutical substance in a pharmaceutical formulation.
PAPER
Bioorganic & Medicinal Chemistry (2010), 18(10), 3606-3617.
https://www.sciencedirect.com/science/article/pii/S0968089610002452?via%3Dihub
PAPER
RSC Drug Discovery Series (2011), 4(Accounts in Drug Discovery), 215-237.
PAPER
https://aac.asm.org/content/52/2/648
REFERENCES
1: Rai MA, Pannek S, Fichtenbaum CJ. Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opin Emerg Drugs. 2018 May 10:1-9. doi: 10.1080/14728214.2018.1474202. [Epub ahead of print] PubMed PMID: 29737220.
2: Mackman RL. Anti-HIV Nucleoside Phosphonate GS-9148 and Its Prodrug GS-9131: Scale Up of a 2′-F Modified Cyclic Nucleoside Phosphonate and Synthesis of Selected Amidate Prodrugs. Curr Protoc Nucleic Acid Chem. 2014 Mar 26;56:14.10.1-21. doi: 10.1002/0471142700.nc1410s56. Review. PubMed PMID: 25606977.
3: De Clercq E. The clinical potential of the acyclic (and cyclic) nucleoside phosphonates: the magic of the phosphonate bond. Biochem Pharmacol. 2011 Jul 15;82(2):99-109. doi: 10.1016/j.bcp.2011.03.027. Epub 2011 Apr 8. Review. PubMed PMID: 21501598.
4: Mackman RL, Ray AS, Hui HC, Zhang L, Birkus G, Boojamra CG, Desai MC, Douglas JL, Gao Y, Grant D, Laflamme G, Lin KY, Markevitch DY, Mishra R, McDermott M, Pakdaman R, Petrakovsky OV, Vela JE, Cihlar T. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg Med Chem. 2010 May 15;18(10):3606-17. doi: 10.1016/j.bmc.2010.03.041. Epub 2010 Mar 27. PubMed PMID: 20409721.
5: Cihlar T, Laflamme G, Fisher R, Carey AC, Vela JE, Mackman R, Ray AS. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother. 2009 Jan;53(1):150-6. doi: 10.1128/AAC.01183-08. Epub 2008 Nov 10. PubMed PMID: 19001108; PubMed Central PMCID: PMC2612154.
6: Cihlar T, Ray AS, Boojamra CG, Zhang L, Hui H, Laflamme G, Vela JE, Grant D, Chen J, Myrick F, White KL, Gao Y, Lin KY, Douglas JL, Parkin NT, Carey A, Pakdaman R, Mackman RL. Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131. Antimicrob Agents Chemother. 2008 Feb;52(2):655-65. Epub 2007 Dec 3. PubMed PMID: 18056282; PubMed Central PMCID: PMC2224772.
7: Ray AS, Vela JE, Boojamra CG, Zhang L, Hui H, Callebaut C, Stray K, Lin KY, Gao Y, Mackman RL, Cihlar T. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent. Antimicrob Agents Chemother. 2008 Feb;52(2):648-54. Epub 2007 Dec 3. PubMed PMID: 18056281; PubMed Central PMCID: PMC2224749.
8: Birkus G, Wang R, Liu X, Kutty N, MacArthur H, Cihlar T, Gibbs C, Swaminathan S, Lee W, McDermott M. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother. 2007 Feb;51(2):543-50. Epub 2006 Dec 4. PubMed PMID: 17145787; PubMed Central PMCID: PMC1797775.
//////////////Rovafovir etalafenamide, GS-9131, PHASE 2
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