Denufosol

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Denufosol

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Denufosol
Clinical data

Other names	INS37217 2'-Desoxycytidine (5')tetraphospho(5')uridine
Routes of administration	Inhalation
ATC code	none
Legal status
Legal status	Investigational
Identifiers
IUPAC name [[(3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate
CAS Number	211448-85-0^Y
PubChem CID	9875516
ChemSpider	8051201
UNII	5PC250KSSH
ChEMBL	ChEMBL1767407
CompTox Dashboard (EPA)	DTXSID50870235
Chemical and physical data
Formula	C₁₈H₂₇N₅O₂₁P₄
Molar mass	773.323 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C1[C@@H]([C@H](O[C@H]1N2C=CC(=NC2=O)N)COP(=O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)OC[C@@H]3[C@H]([C@H]([C@@H](O3)N4C=CC(=O)NC4=O)O)O)O
InChI InChI=1S/C18H27N5O21P4/c19-11-1-3-22(17(28)20-11)13-5-8(24)9(40-13)6-38-45(30,31)42-47(34,35)44-48(36,37)43-46(32,33)39-7-10-14(26)15(27)16(41-10)23-4-2-12(25)21-18(23)29/h1-4,8-10,13-16,24,26-27H,5-7H2,(H,30,31)(H,32,33)(H,34,35)(H,36,37)(H2,19,20,28)(H,21,25,29)/t8-,9+,10+,13+,14+,15+,16+/m0/s1 Key:FPNPSEMJLALQSA-MIYUEGBISA-N
(verify)

Denufosol (INN) is an inhaled drug for the treatment of cystic fibrosis, being developed by Inspire Pharmaceuticals and sponsored by the Cystic Fibrosis Foundation. It was tested in two Phase III clinical trials, TIGER-1 and TIGER-2. Initially, in the first Phase III trial, TIGER-1, the compound showed significant results as compared with placebo.^[1] In the second Phase III trial, TIGER-2, the compound did not meet the primary endpoint, a significant change in baseline FEV1 (forced expiratory volume in one second) at the week 48 endpoint as compared to placebo.^[2] As of 2011, no additional clinical studies are being conducted with the compound.

The drug was also investigated for the treatment of retinal detachment and other retinal diseases, but trials were terminated in 2006.^[3]

Application

[edit]

In Phase III studies, denufosol was orally inhaled by patients with cystic fibrosis three times a day using a jet nebulizer. To be effective, it had to reach the deeper parts of the lung (bronchioles), making it unsuitable for children under five years of age.^[4]

Mechanism of action

[edit]

Cystic fibrosis is characterised by a defect of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) on epithelial cells in the lungs. The CFTR regulates the components of sweat, digestive juices, and mucus. Defects lead to a viscous, dehydrated mucus, hindering mucociliary clearance. Denufosol is an agonist at the P2Y₂ subtype of purinergic receptors which via its associated G protein leads to activation of alternative chloride channel. Activating this alternate chloride channel theoretically increases ion transport in cystic fibrosis patients which compensates the effects caused by the non-functioning CFTR.^[5]

Chemistry

[edit]

Denufosol consists of two nucleosides (composed of a nucleobase and a sugar each), deoxycytidine and uridine, linked on their sugars by four units of phosphoric acid. It is used in form of its tetrasodium salt.^{[citation needed]}

References

[edit]

^ Accurso FJ, Moss RB, Wilmott RW, Anbar RD, Schaberg AE, Durham TA, Ramsey BW (March 2011). "Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function". American Journal of Respiratory and Critical Care Medicine. 183 (5): 627–34. doi:10.1164/rccm.201008-1267OC. PMID 21169471.
^ "Inspire Announces Results of Second Phase 3 Trial with Denufosol for Cystic Fibrosis". Archived from the original on 2012-03-22. Retrieved 2011-04-03.
^ Clinical trial number NCT00083967 for "Study of Denufosol (INS37217) in Subjects With Rhegmatogenous Retinal Detachment" at ClinicalTrials.gov
^ Spreitzer H (14 March 2011). "Neue Wirkstoffe – Denufosol". Österreichische Apothekerzeitung (in German) (6/2011): 10.
^ Kellerman D, Rossi Mospan A, Engels J, Schaberg A, Gorden J, Smiley L (August 2008). "Denufosol: a review of studies with inhaled P2Y(2) agonists that led to Phase 3". Pulmonary Pharmacology & Therapeutics. 21 (4): 600–7. doi:10.1016/j.pupt.2007.12.003. PMID 18276176.

Purine receptor modulators

Receptor
(ligands)

P0 (adenine)

Agonists: 8-Aminoadenine
Adenine

P1
(adenosine)

Agonists: 2-(1-Hexynyl)-N-methyladenosine
2-Cl-IB-MECA
2-Chloroadenosine
2'-MeCCPA
4'-O-β-D-Glucosyl-9-O-(6''-deoxysaccharosyl)olivil
5'-N-ethylcarboxamidoadenosine
Adenosine
ADP
AMP
Apadenoson
ATL-146e
ATP
BAY 60–6583
Binodenoson
Capadenoson
CCPA
CGS-21680
CP-532,903
CV-1808
Evodenoson
GR 79236
HENECA
LUF-5835
LUF-5845
N⁶-Cyclopentyladenosine
Namodenoson
NECA
Neladenoson dalanate
Piclidenoson
Regadenoson
SDZ WAG 994
Selodenoson
Sonedenoson
Tecadenoson
Trabodenoson
UK-432,097

Antagonists: 3-Chlorostyrylcaffeine (CSC)
7-Methylxanthine
8-Chlorotheophylline
8-Phenyl-1,3-dipropylxanthine
8-Phenyltheophylline
Acefylline
Aminophylline
ATL-444
AZD-4635
Bamifylline
Cafedrine
Caffeine
Caffeine citrate
Cartazolate
CGH-2466
CGS-15943
Choline theophyllinate
Ciforadenant
CPX
CVT-6883
Dimethazan
DMPX
DPCPX
Dyphylline
Enprofylline
Etazolate
Etrumadenant
Fenethylline
IBMX
Imaradenant
Inupadenant
ISAM-140
ISAM-R316
Isovaleric acid
Istradefylline
KF-26777
Lu AA41063
Lu AA47070
MRE3008F20
MRS-1191
MRS-1220
MRS-1334
MRS-1523
MRS-1706
MRS-1754
MRS-3777
MSX-2
MSX-3
MSX-4
Muvadenant
Paraxanthine
Pentoxifylline
Preladenant
Propentofylline
Proxyphylline
PSB-10
PSB-11
PSB-36
PSB-603
PSB-788
PSB-1115
PSB-1901
Reversine
Rolofylline
SCH-442,416
SCH-58261
Sipagladenant
Taminadenant
Theacrine
Theobromine
Theodrenaline
Theophylline
Tozadenant
Tracazolate
Vipadenant
VUF-5574
ZM-241,385

P2
(nucleotide)

P2X
(ATP)

Antagonists: 5-BDBD
A-317491
A-438079
A-740003
A-804598
A-839977
AF-353
AZ-10606120
AZ-11645373
BBG
Calcium
Calmidazolium
Chelerythrine
Copper
Emodin (Rheum officinale)
Evans blue
Gefapixant
GW-791343
HMA
Ip5I
isoPPADS
JNJ-47965567
KN-04
KN-62
Magnesium
MRS-2159
NF-023
NF-110
NF-157
NF-279
NF-449
Opiranserin (VVZ-149)
Oxidized-ATP
Phenol Red
Phenolphthalein
PPADS
PPNDS
PSB-12062
Puerarin (Radix puerariae)
Purotoxin 1
RB-2
Ro 0437626
Ro 51
RO-3
Sodium ferulate (Angelica sinensis, Ligusticum wallichii)
Suramin
TC-P 262
Tetramethylpyrazine (ligustrazine) (Ligusticum wallichii)
TNP-ATP
Zinc

P2Y

Transporter
(blockers)

CNTsTooltip Concentrative nucleoside transporters	6-Hydroxy-7-methoxyflavone Adenosine dMeThPmR Estradiol KGO-2142 KGO-2173 MeThPmR Phloridzin Progesterone
ENTsTooltip Equilibrative nucleoside transporters	Barbiturates Benzodiazepines Cilostazol Dilazep Dipyridamole Estradiol Ethanol Hexobendine NBMPR Pentoxifylline Progesterone Propentofylline
PMATTooltip Plasma membrane monoamine transporter	Decynium-22

Enzyme
(inhibitors)

XOTooltip Xanthine oxidase	Allopurinol Amflutizole Benzbromarone Caffeic acid Cinnamaldehyde Cinnamomum osmophloeum Febuxostat Myo-inositol Kaempferol Myricetin Niraxostat Oxipurinol Phytic acid Pistacia integerrima Propolis Quercetin Tisopurine Topiroxostat
Others	Aminopterin Azathioprine Methotrexate Mycophenolic acid Pemetrexed Pralatrexate Many others

Others

Others: Chrysophanol (rhubarb)

See also: Receptor/signaling modulators

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