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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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Rovafovir Etalafenamide

2D chemical structure of 912809-27-9

Rovafovir etalafenamide



 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.



WO 2006110157

WO 2008103949

WO 2010005986


WO 2012159047




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.


Bioorganic & Medicinal Chemistry (2010), 18(10), 3606-3617.

Image result for Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

Image result for Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148


 RSC Drug Discovery Series (2011), 4(Accounts in Drug Discovery), 215-237.


Image result for GS-9131


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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