ADAFOSBUVIR

AL335; ALS-335; JNJ-64146212 , D11364

Propan-2-yl N-((P5’S)-4′-fluoro-2′-C-methyl-p-o-phenyl- 5′-uridylyl)-L-alaninate

propan-2-yl (2S)-2-{[(S)-{[(2S,3S,4R,5R)-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-2-fluoro-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate

Isopropyl (2S)-2-{[(S)-{[(2S,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-2-fluoro-3,4-dihydroxy-4-methyltetrahydro-2-furanyl]methoxy}(phenoxy)phosphoryl]amino}propanoate (non-preferred name

Propan-2-yl N-((P5’S)-4′-fluoro-2′-C-methyl-p-o-phenyl- 5′-uridylyl)-L-alaninate

545.5 g/mol, C₂₂H₂₉FN₃O₁₀P

CAS Registry Number 1613589-09-5

Adafosbuvir is under investigation in clinical trial NCT02894905 (A Study to Evaluate the Effect of Renal Impairment on the Pharmacokinetics of AL-335).

• Originator Alios BioPharma
• Developer Alios BioPharma; Janssen
• Class Antivirals; Pyrimidine nucleotides; Uracil nucleotides
• Mechanism of Action Hepatitis C virus NS 5 protein inhibitors

• Phase II Hepatitis C

• 28 Oct 2019 No recent reports of development identified for phase-I development in Hepatitis-C(In volunteers) in USA (PO)
• 28 Sep 2018 No recent reports of development identified for phase-I development in Hepatitis-C in France (PO)
• 28 Sep 2018 No recent reports of development identified for phase-I development in Hepatitis-C in Georgia (PO)

Adafosbuvir (AL 335), a monophosphate prodrug, is being developed by Alios BioPharma (a subsidiary of Johnson & Johnson) for the treatment of hepatitis C virus (HCV) infections. Adafosbuvir acts a uridine-based nucleotide analogue polymerase inhibitor. Clinical development is underway in New Zealand, Japan, the UK, the US, France, Georgia, Mauritius and Moldova.

Adafosbuvir has emerged from the company’s research programme focused on developing anti-viral nucleotides for the treatment of HCV infections , In November 2014, Alios BioPharma was acquired by Johnson & Johnson As at September 2018, no recent reports of development had been identified for phase-I development in Hepatitis-C in France (PO), Georgia (PO).

As at October 2019, no recent reports of development had been identified for phase-I development in Hepatitis-C (In volunteers) in USA (PO).

useful for the treatment of hepatitis C viral infections, assignaed to Janssen Pharmaceuticals Inc and Achillion Pharmaceuticals Inc . Janssen Pharmaceuticals, following Johnson & Johnson’s acquisition of Alios , was developing adafosbuvir, a uridine (pyrimidine) nucleotide analog, from a series of back-up compounds, that acts by inhibiting HCV NS5B polymerase, for the potential treatment of HCV infection.

As of December 2019, AL-335 dose increased from 400 to 800 mg qd in the presence of reduced simeprevir and odalasvlr doses increased ALS-022227 less than dose proportionally. However, this effect was minimal in the absence of slmeprevir [1973148]. Also, the company was also developing JNJ-4178 , a triple combination of adafosbuvir, odalasvir and simeprevir for the same indication.

McGuigan phosphoramidate nucleotide prodrugs. (a) Sofosbuvir (GS-7977) (Sp isomer), (b) BMS-986094 (Rp and Sp isomer mixture), (c) Adafosbuvir (AL-335) (Sp isomer), (d) ACH-3422*, and (e) MIV-802* (Sp isomer)

https://www.semanticscholar.org/paper/Current-and-future-use-of-nucleo(s)tide-prodrugs-in-Dousson/03919c0a17f25575a5e2b8dc56c70b1e27eea2e6

Figure 3. Clinical and preclinical 30,50-CPO prodrug. (a) GS-0938 (Rp isomer) and (b) IDX19368 (Sp isomer).

PAPER

Journal of Medicinal Chemistry (2019), 62(9), 4555-4570.

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b00143

We report the synthesis and biological evaluation of a series of 4′-fluoro-2′-C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC₅₀values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC₅₀ values as low as 20 nM. A lead compound AL-335(53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.

PATENT

WO 2014209979

WO2014100505

Family members of the product case of adafosbuvir, WO2014100505 , expire in the US in December 2033.

PATENT

US 20150368286

WO 2015054465

PATENT

WO2017059147 ( US20170087174 ), claiming combination comprising simeprevir , odalasvir and AL-335

PATENT

WO-2019237297

Process for preparing AL-335 (also known as adafosbuvir) and its intermediates. AL-355 is a nucleoside inhibitor of NS3B polymerase, which plays an important role in the replication of the hepatitis C virus.

A huge amount of research has gone into discovery of a number of types of direct-acting antivirals against HCV, including NS5B polymerase inhibitors. Within this category, there exists both non-nucleoside and nucleoside types, and in relation to the latter category the following compound, also known as AL-335 (adafosbuvir) has been discovered and is currently in development:

Various processes are already known to prepare AL-335, including those described in e.g. international patent applications WO 2014/100505 and WO 2015/200216 and US patent application US 2015/0368286, where amongst other routes the following synthetic schemes are disclosed:

Compound 1 (1.0 equiv) was dissolved in THF (10 L/kg) and cooled down to -8℃. Compound 2 (1.0 equiv) was then added to the mixture. Triethylamine was then added dropwise slowly (the longer the period over which triethylamine is added, the better the filtration will be vis-à-vis scale) . The reaction was left stirring 30 minutes after the end of addition and then warmed up to 0℃. Cyclohexane (10 L/kg) was then added to the reaction mixture and stirred for 30 min. The heterogenous mixture was then filtered, concentrated to 6V and cooled down to 0℃. After one hour stirring, the mixture was filtered, assayed and stored under nitrogen. The Compound 3 (as a mixture of configurations at the phosphorous atoms) so formed was thus used as such in the next step, without any further purification.

Compound 4 may be prepared in accordance with the procedures described in international patent application WO 2015/200216. Compound 4 (1.0 equiv) was then dissolved in THF (10 L/kg) and cooled down to -25℃. iPrMgCl (2M in THF) was added slowly over one hour and the resulting mixture was stirred for one hour. The Compound 3 solution previously made (see above) was then added dropwise at -25℃ and the mixture was stirred for 5h at that temperature before being warmed to -5℃ and stirred for 10 additional hours at that temperature. Once the reaction was complete, the reaction was warmed up to 5℃ and an aqueous solution of NH ₄Cl (5L/kg -9 w/w%) was added slowly over 30 minutes. After phase separation, the organic layer was washed with aqueous NaHCO ₃ solution (5L/kg -10 w/w%) and twice with aqueous NaCl solution (5L/kg -10 w/w%) . After solvent switch to acetonitrile, the reaction was assayed and stored under nitrogen and used as such in the next step.

/////////////ADAFOSBUVIR, AL335, ALS-335, JNJ-64146212, Alios BioPharma,  Janssen,  hepatitis C viral infections, D11364, адафосбувир , أدافوسبوفير , PHASE 2

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