Chemistry:RPL-554
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| Other names | 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 |
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| Formula | C26H31N5O4 |
| Molar mass | 477.565 g·mol−1 |
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RPL-554 (LS-193,855) is a drug candidate for respiratory diseases. It is an analog of trequinsin and, like trequinsin, is a highly selective inhibitor of the phosphodiesterase enzyme, PDE3; indeed, it is >3000-times more potent against PDE3 than PDE4.[1] As of October 2015, inhaled RPL-554 delivered via a nebulizer was in development for COPD and had been studied in asthma.[2]
PDE3 inhibitors act as bronchodilators, while PDE4 inhibitors have an anti-inflammatory effect.[1][3]
RPL554 was part of a family of compounds invented by Sir David Jack, former head of R&D for GlaxoSmithKline, and Alexander Oxford, a medicinal chemist; the patents on their work were assigned to Vernalis plc.[4][5][6]:19-20
In 2005, Rhinopharma Ltd, acquired the rights to the intellectual property from Vernalis.[6]:19-20 Rhinopharma was a startup founded in Vancouver, Canada in 2004 by Michael Walker, Clive Page, and David Saint, to discover and develop drugs for chronic respiratory diseases,[6]:16 and intended to develop RPL-554, delivered with an inhaler, first for allergic rhinitis, then asthma, then for COPD.[6]:16-17 RPL554 was synthesized at a contract research organization, under the supervision of Oxford, and was studied in collaboration with Page's lab at King’s College, London.[1] In 2006 Rhinopharma recapitalized and was renamed Verona Pharma plc.[6]
References
- ↑ 1.0 1.1 1.2 "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-aisoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]"]. The Journal of Pharmacology and Experimental Therapeutics 318 (2): 840–8. August 2006. doi:10.1124/jpet.105.099192. PMID 16682455. http://pdfs.semanticscholar.org/aa0b/e9800b0df6655f3e885489d927352158f782.pdf.
- ↑ Taylor, Nick Paul (1 October 2015). "Verona sets sights on PhIIb after COPD drug comes through early trial". FierceBiotech. http://www.fiercebiotech.com/story/verona-sets-sights-phiib-after-copd-drug-comes-through-early-trial/2015-10-01.
- ↑ "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 310 (1): L59-70. January 2016. doi:10.1152/ajplung.00324.2015. PMID 26545902.
- ↑ Oxford, Alexander William & David Jack, "Derivatives of pyrimido[6,1-a]isoquinolin-4-one", EP patent 1165558, published 2002-01-02
- ↑ "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]". The Journal of Pharmacology and Experimental Therapeutics 318 (2): 840–848. August 2006. doi:10.1124/jpet.105.099192. PMID 16682455.
- ↑ 6.0 6.1 6.2 6.3 6.4 "Proposed Acquisition of Rhinopharma". Isis Resources plc. 23 August 2006. http://www.veronapharma.com/joomla/images/Documents/verona%20pharma%20admission%20doc.pdf.
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