Ensifentrine
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{{Drugbox | verifiedrevid = 461481983 | IUPAC_name = N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea | image = RPL554.png | width = 240
| tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration =
| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =
| CAS_number_Ref = 
| CAS_number =
| ATC_prefix =
| ATC_suffix =
| PubChem = 9934746
| DrugBank_Ref =
| DrugBank =
| ChemSpiderID_Ref =
| ChemSpiderID = 8110374
| InChI = 1/C26H31N5O4/c1-15-10-16(2)24(17(3)11-15)29-23-14-20-19-13-22(35-5)21(34-4)12-18(19)6-8-30(20)26(33)31(23)9-7-28-25(27)32/h10-14H,6-9H2,1-5H3,(H3,27,28,32)/b29-23+
| InChIKey = CSOBIBXVIYAXFM-BYNJWEBRBJ
| StdInChI_Ref =
| StdInChI = 1S/C26H31N5O4/c1-15-10-16(2)24(17(3)11-15)29-23-14-20-19-13-22(35-5)21(34-4)12-18(19)6-8-30(20)26(33)31(23)9-7-28-25(27)32/h10-14H,6-9H2,1-5H3,(H3,27,28,32)/b29-23+
| StdInChIKey_Ref =
| StdInChIKey = CSOBIBXVIYAXFM-BYNJWEBRSA-N
| C=26 | H=31 | N=5 | O=4 | molecular_weight = 477.554 g/mol | smiles = Cc3cc(C)cc(C)c3N=c2cc1-c(cc4OC)c(cc4OC)CCn1c(=O)n2CCNC(N)=O | synonyms = 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one }}
RPL-554 (LS-193,855) is a drug which acts as a long-acting inhibitor of the phosphodiesterase enzymes PDE-3 and PDE-4, producing both bronchodilator and anti-inflammatory effects.[1]
RPL554 was originally developed at The Sackler Institute of Pulmonary Pharmacology, King’s College, London, as a result of extensive work led by Professor Clive Page, Sir David Jack and Dr Alec Oxford.[2] [3]
RPL554 is now being developed by Verona Pharma plc as a potential treatment for :-
RPL554 is currently in Phase II clinical trials for asthma[4] and COPD.[5]
Verona Pharma has recently received a Venture and Innovation Award from the Cystic Fibrosis Trust.[6]
History
RPL554 was discovered and initially tested is the result of extensive work carried out at The Sackler Institute of Pulmonary Pharmacology, King’s College London.
Notable people involved include :-
- Professor Clive Page
- Sir David Jack[7]
- Dr Alec Oxford
The team made around 200 molecules before hitting on RPL554 as the molecule with the desired properties..[8]
Mechanism of action
Bronchodilation
The molecule RPL554 is a selective, long-acting dual inhibitor of the enzymes PDE3 / PDE4.[citation needed]
Mucociliary clearance for cystic fibrosis
By inhibiting cAMP breakdown, PDE inhibitors stimulate cystic fibrosis transmembrane conductance regulator (CFTR).[9]
RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.[9]
References
- ^ Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 (9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl) -3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-4-one) and RPL565 (6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido(6,1-a)isoquinolin-4-one). Journal of Pharmacology and Experimental Therapeutics 2006; 318(2):840-848.
- ^ "Revolutionary asthma treatment". King's College London. Retrieved 25 January 2016.
- ^ "New class of drug shows promise for treating asthma and COPD". King's College London. Retrieved 25 January 2016.
- ^ Cite error: The named reference
NCT02427165_CTwas invoked but never defined (see the help page). - ^ Cite error: The named reference
NCT02542254_CTwas invoked but never defined (see the help page). - ^ "Trust award for further research into pipeline drug". Cystic Fibrosis Trust (Charity). Retrieved 25 January 2016.
- ^ "Sir David Jack, who has died aged 87, was the scientific brain behind the rise of the pharmaceuticals company Glaxo". Telegraph Newspaper. Retrieved 27 February 2016.
- ^ "Asthma and hay fever drug tested". BBC News Report. Retrieved 25 January 2016.
- ^ a b "The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia". American Journal of Physiology - Lung Cellular and Molecular Physiology (Published 6 November 2015). Retrieved 25 January 2016.