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Showing posts with label Part 2/2. Show all posts
Showing posts with label Part 2/2. Show all posts

Monday, 17 August 2015

IVACAFTOR PART 2/2




Ivacaftor.svg

IVACAFTOR
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3-carboxamide
N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
Molecular formula: C24H28N2O3
CAS#: 873054-44-5
MW: 392.49
Melting Point: 292-295°C
NMR——-http://file.selleckchem.com/downloads/nmr/s114401-ivacaftor-vx770-hnmr-selleck.pdf
COSY NMR PREDICT



COSY
Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved for patients with a certain mutation of cystic fibrosis, which accounts for 4–5% cases of cystic fibrosis.[1][2] Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with theCystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease.[3] Called “the most important new drug of 2012″,[4] and “a wonder drug”[5] it is one of the most expensive drugs, costing over US$300,000 per year, which has led to criticism of Vertex for the high cost.
Ivacaftor (VX-770, Kalydeco) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively
Ivacaftor is a white to off-white crystalline solid. It is freely soluble in methylethyl ketone/water mixture, soluble in 2-methyl tetrahydrofuran and PEG 400, slightly soluble in methanol, acetone and ethanol and practically insoluble in water and buffers with pH 1.0 – 7.0.  The active substance shows polymorphism. Mixture of two major crystalline neat polymorphic forms (B and C) is obtained when manufactured by the commercial manufacturing process described. Form C is the most thermodynamically stable neat form. The polymorphic form is not of concern during the synthesis of the active substance, as the active substance is fully dissolved during manufacture of the finished product…………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002494/WC500130766.pdf
Quality by Design (QbD) approach has been used in product and process development of ivacaftor. For the active substance synthesis, a combination of multivariate analyses and range-finding studies was used to define a design space for each step. All parameters with a potential impact on critical quality attributes (CQAs) of the active substance were identified and thoroughly investigated. The Applicant has proposed a combination of proven acceptable ranges (PARs) and design spaces (DSs) for the manufacturing process of the active substance. Design spaces have been developed at small laboratory scales (0.5-20 g) and the scale-up to production levels (100 kg) is wide (x 5000, x 10.000…).

Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator (CFTR), which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. One such defect is the G551D mutation, in which the amino acid glycine (G) in position 551 is replaced with aspartic acid (D). G551D is characterized by a dysfunctional CFTR protein on the cell surface. In the case of G551D, the protein is trafficked to the correct area, the epithelial cell surface, but once there the protein cannot transport chloride through the channel. Ivacaftor, a CFTR potentiator, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.[6][7][8]

HPLC
HPLC

Economics

The cost of ivacaftor is $311,000 per year, roughly similar to the price of other drugs for extremely rare diseases.[18] In the first 9 months of its second year on the market (2014), ivacaftor sales were $339M, representing 54% of Vertex’s product sales revenue. During the same period, drug development expenses were $458M, most of which was spent on cystic fibrosis-related research.[19]
An editorial in JAMA called the price of ivacaftor “exorbitant”, citing the support by the Cystic Fibrosis Foundation in its development and the contribution made by fundamental scientific research performed by the National Institutes of Health and relied upon by Vertex in its cystic fibrosis drug discovery programs.[20] The company responded in an email that “while publicly funded academic research provided important early understanding of the cause of cystic fibrosis, it took Vertex scientists 14 years of their own research, funded mostly by the company, before the drug won approval.”[21]
The Cystic Fibrosis Foundation, a non-profit organization dedicated to improving healthcare for people with cystic fibrosis, provided $150 million of the funding for the development for ivacaftor in exchange for royalty rights in the event that the drug was successfully developed and commercialized. In 2014, the Foundation sold these royalty rights for $3.3 billion. The Foundation has stated that it intends to spend these funds in support of further research.[22][23]
Vertex said it would make the drug available free to patients in the United States with no insurance and a household income of under $150,000.[24] In 2012, 24 US doctors and researchers involved in the development of the drug wrote to Vertex to protest the price of the drug, which had been set at about $300,000 per year. In the UK, the company provided the drug free for a limited time for certain patients, then left the hospitals to decide whether to continue to pay for it for those patients. UK agencies estimated the cost per quality adjusted life year (QALY) at between £335,000 and £1,274,000 —well above the National Institute for Health and Care Excellence thresholds.[25]
The drug was not covered under the Ontario Drug Benefit plan until June 2014 when the Province of Ontario and the manufacturer negotiated for what “Ontario Health MinisterDeb Matthews had called a “fair price” for taxpayers”. The negotiations took 16 months and it was estimated that around 20 Ontarians required the drug at the time.[26]
The province of Alberta began covering the drug in July 2014, and in September the province of Saskatchewan became the third province to include it in its provincial drug plan.[27]
Government delays in agreeing to provide ivacaftor in national health plans led to patient group protests in Wales,[28][29] England,[30] and Australia.[31]

.







PURE

NMR GRAPH FROM NET

NMR

NMR ABMOLE


NMR CHEMDOODLE
1H NMR PREDICT
molbase 1h graph molbase 1h val

13C NMR PREDICT
molbase 13c graph molbase 13cval
1H NMR PREDICT VIA NMRDB
H EXPLODED
1H NMR DB VAL

1H NMR DB GRAPH

13C NMR VIA NMRDB
13C NMR DB VAL 13C NMR DBGRAPH IVACAFTOR IMAGE



…………
JMC
http://pubs.acs.org/doi/pdf/10.1021/jm5012808
N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
(0.2 g, 71%). 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.82 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.84−7.78 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.56−7.45 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H).
HRMS-ESI (m/z): [M + H]+ calcd for C24H28N2O3, 393.2178; found, 393.2164.
………
VERTEX PHARMACEUTICALS INCORPORATED Patent: US2008/90864 A1, 2008 ; Location in patent: Page/Page column 8; 9 ;
Heterocycles, , vol. 89, # 4 p. 1035 – 1040
US2011/230519 A1, ;



References

  1.  Jones AM, Helm JM (October 2009). “Emerging treatments in cystic fibrosis”. Drugs 69(14): 1903–10. doi:10.2165/11318500-000000000-00000. PMID 19747007.
  2.  McPhail GL, Clancy JP (April 2013). “Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis”. Drugs Today 49 (4): 253–60.doi:10.1358/dot.2013.49.4.1940984. PMID 23616952.
  3.  “Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation”. Press Release. Cystic Fibrosis Foundation. 2011-02-23.
  4.  “The Most Important New Drug Of 2012 – Forbes”.
  5. “The $300,000 Drug – NYTimes.com”.
  6.  Eckford PD, Li C, Ramjeesingh M, Bear CE (October 2012). “Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner”. J. Biol. Chem. 287 (44): 36639–49.doi:10.1074/jbc.M112.393637. PMID 22942289.
  7. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P (November 2009).“Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770″.Proc. Natl. Acad. Sci. U.S.A. 106 (44): 18825–30. doi:10.1073/pnas.0904709106.PMC 2773991. PMID 19846789.
  8.  Sloane PA, Rowe SM (November 2010). “Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis”. Curr Opin Pulm Med 16(6): 591–7. doi:10.1097/MCP.0b013e32833f1d00. PMID 20829696.
  9.  “pi.vrtx.com” (PDF).
  10.  “FAQs about the Cause, Diagnosis, Treatment of Cystic Fibrosis & More | CF Foundation”.
  11.  Bobadilla JL, Macek M, Fine JP, Farrell PM (June 2002). “Cystic fibrosis: a worldwide analysis of CFTR mutations–correlation with incidence data and application to screening”.Hum. Mutat. 19 (6): 575–606. doi:10.1002/humu.10041. PMID 12007216.
  12. “pi.vrtx.com” (PDF).
  13.  “pi.vrtx.com” (PDF).
  14.  http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_kalydeco_155318-eng.php
  15.  Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW (November 2010). “Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation”. N. Engl. J. Med. 363(21): 1991–2003. doi:10.1056/NEJMoa0909825. PMC 3148255. PMID 21083385.
  16.  “Kalydeco: Annex I: Summary of product characteristics” (PDF). European Medicines Agency.
  17.  “pi.vrtx.com” (PDF).
  18.  “F.D.A. Approves New Cystic Fibrosis Drug”. New York Times. January 31, 2012. Retrieved 2015-02-10.
  19.  “Vertex Pharmaceuticals 10-Q, Quarter ending September 30, 2014″. Retrieved2015-02-10.
  20.  Brian P. O’Sullivan; David M. Orenstein; Carlos E. Milla (October 2, 2013). “Viewpoint: Pricing for Orphan Drugs: Will the Market Bear What Society Cannot?”. JAMA. 310 (13): 1343–1344. doi:10.1001/jama.2013.278129.
  21.  “Cystic Fibrosis: Charity and Industry Partner for Profit”. MedPage Today. May 19, 2013. Retrieved 2015-02-10.
  22.  “CF Foundation Cashes Out on Kalydeco in $3.3B Sale to Royalty Pharma | Xconomy”.
  23.  “CF Foundation Royalty Sale Will Be Transformational for People with CF”.
  24.  “FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis” (Press release). Cambridge, Massachusetts: Vertex Pharmaceuticals. 2012-01-31. Retrieved 2014-02-01.
  25.  Deborah Cohen; James Raftery (12 February 2014). “Orphan Drugs: Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding”. BMJ348: g1445. doi:10.1136/bmj.g1445.
  26. Ferguson, Rob (June 20, 2014). “OHIP to cover cystic fibrosis drug Kalydeco”. The Toronto Star. Retrieved June 20, 2014.
  27.  “Saskatchewan to cover $300K cystic fibrosis drug Kalydeco”. CBC News. 2014-08-28. Retrieved 2014-08-28.
  28.  “Plea for Kalydeco drug to be introduced | Wales – ITV News”.
  29.  “BBC News – Cystic fibrosis: New drug Kalydeco refused for Welsh NHS”.
  30.  “Protests at Birmingham Hospital as cystic fibrosis sufferer is denied life-saving drug – Birmingham Mail”.
  31.  “Kalydeco breakthrough: Plea for life-saving medicine proves a winner | Manning River Times”.

External links


US4556658 * Apr 24, 1984 Dec 3, 1985 Bayer Aktiengesellschaft 7-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids and antibacterial agents containing these compounds
US4822801 * Oct 20, 1986 Apr 18, 1989 Warner-Lambert Company 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents
US20060074075 * Jun 24, 2005 Apr 6, 2006 Sara Hadida-Ruah Modulators of ATP-binding cassette transporters
US20100267768 * Mar 19, 2010 Oct 21, 2010 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US20110064811 * Dec 28, 2006 Mar 17, 2011 Patricia Hurter Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide



Systematic (IUPAC) name
N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
Clinical data
Trade names Kalydeco
Licence data US FDA:link
Pregnancy
category
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Protein binding 99%
Metabolism CYP3A
Biological half-life 12 hrs (single dose)
Excretion 88% faeces
Identifiers
CAS Registry Number 873054-44-5 
ATC code R07AX02
PubChem CID: 16220172
IUPHAR/BPS 4342
ChemSpider 17347474 Yes
UNII 1Y740ILL1Z Yes
ChEBI CHEBI:66901 
Synonyms VX-770
Chemical data
Formula C24H28N2O3
Molecular mass 392.490 g/mol
//////Ivacaftor,  Kalydeco,  VX-770
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