New Drug Approvals

Home » hepatitis C viral infections » ADAFOSBUVIR, адафосбувир , أدافوسبوفير ,

ADAFOSBUVIR, адафосбувир , أدافوسبوفير ,

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Recent Posts

Blog Stats

  • 3,093,073 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,543 other followers

add to any

Share

Adafosbuvir.png

ChemSpider 2D Image | adafosbuvir | C22H29FN3O10P

Thumb

img

2D chemical structure of 1613589-09-5

ADAFOSBUVIR

AL335; ALS-335; JNJ-64146212 , D11364

адафосбувир [Russian] [INN]
أدافوسبوفير [Arabic] [INN]

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.

Figure 2. 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). *Potential structure from Deshpande,31 Kalayanov et al.,45 and Andersson.46

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).

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.

Abstract Image

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.

Hepatitis C virus (HCV) , a member of the Flaviviridae family of viruses in the hepacivirus genus, is the leading cause of chronic liver disease worldwide. Recent estimates report the global hepatitis C prevalence at around 2.4%with up to 170 million people thought to be chronically infected. Although the development of diagnostics and blood screening has considerably reduced the rate of new infections, HCV remains a global health burden due to its chronic nature and its potential for long-term liver damage. It is now known that HCV has the ability to incorporate into the host’s genome.
The hepatitis C virus genome is a small positive-sense single stranded RNA enclosed in a nucleocapsid and lipid envelope. It consists of 9.6 kb ribonucleotides, which encodes a large polypeptide of about 3,000 amino acids (Dymock et al. Antiviral Chemistry &Chemotherapy 2000, 11, 79) . Following maturation, this polypeptide is processed into at least ten proteins. NS3/4A serine protease is responsible for the cleavage of the non-structural downstream proteins. NS5A is a zinc-binding proline-rich hydrophilic phosphoprotein which has no apparent enzymatic activity yet has an important function mediating the interaction with other nonstructural viral and cellular proteins. NS5B is an enzyme with polymerase activity that is involved in the synthesis of double-stranded RNA from the single-stranded viral RNA genome, which serves as the template.
NS3/4A serine protease, NS5A and NS5B polymerase are essential for viral replication, and inhibitors are important drug candidates for HCV treatment.
HCV is mainly transmitted by blood contact. Following initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes, but is not directly cytopathic. Over decades, a considerable number of infected persons develop fibrosis, at least 30%develop cirrhosis, 1-4%develop hepatocellular carcinoma, and chronic HCV infection is the leading cause for liver transplantation. HCV is responsible for 50-76%of all liver cancer cases and two thirds of all liver transplants in the developed world. This and the number of patients involved has made HCV the focus of considerable medical research.
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.

Preparation of the compound of AL-335 (adafosbuvir) :
Compound 5 prepared above is essentially a compound of formula (I) as defined herein. The relevant protecting group (e.g. tri-alkyl-silyl group) may be cleaved off under appropriate conditions (e.g. using acid conditions, e.g. HCl conditions, e.g. in between 2 to 2.6 equivalents) to prepare the compound AL-335, also known as adafosbuvir:

/////////////ADAFOSBUVIR, AL335, ALS-335, JNJ-64146212, Alios BioPharma,  Janssen,  hepatitis C viral infections, D11364адафосбувир أدافوسبوفير , PHASE 2

CC(C)OC(=O)[C@H](C)N[P@](=O)(OC[C@@]1(F)O[C@@H](N2C=CC(=O)NC2=O)[C@](C)(O)[C@@H]1O)OC1=CC=CC=C1


1 Comment

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,543 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 30 year tenure till date Dec 2017, 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 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: