RPL-554

Last updated
RPL-554
RPL554.png
Clinical data
Other names9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one
Identifiers
  • N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.245.423 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C26H31N5O4
Molar mass 477.565 g·mol−1
3D model (JSmol)
  • Cc3cc(C)cc(C)c3N=c2cc1-c(cc4OC)c(cc4OC)CCn1c(=O)n2CCNC(N)=O
  • InChI=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+ Yes check.svgY
  • Key:CSOBIBXVIYAXFM-BYNJWEBRSA-N Yes check.svgY
   (verify)

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]

Related Research Articles

<i>Controlled Drugs and Substances Act</i> Canadian federal drug regulation act

The Controlled Drugs and Substances Act is Canada's federal drug control statute. Passed in 1996 under Prime Minister Jean Chrétien's government, it repeals the Narcotic Control Act and Parts III and IV of the Food and Drugs Act, and establishes eight Schedules of controlled substances and two Classes of precursors. It provides that "The Governor in Council may, by order, amend any of Schedules I to VIII by adding to them or deleting from them any item or portion of an item, where the Governor in Council deems the amendment to be necessary in the public interest."

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.

<span class="mw-page-title-main">PDE3 inhibitor</span>

A PDE3 inhibitor is a drug which inhibits the action of the phosphodiesterase enzyme PDE3. They are used for the therapy of acute heart failure and cardiogenic shock.

<span class="mw-page-title-main">Chronic obstructive pulmonary disease</span> Lung disease involving long-term poor airflow

Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. GOLD 2024 defined COPD as a heterogeneous lung condition characterized by chronic respiratory symptoms due to abnormalities of the airways and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.

References

  1. 1 2 3 Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP (August 2006). "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]" (PDF). The Journal of Pharmacology and Experimental Therapeutics . 318 (2): 840–8. doi:10.1124/jpet.105.099192. PMID   16682455. S2CID   15490792. Archived from the original (PDF) on 2019-03-02.
  2. ↑ Taylor NP (1 October 2015). "Verona sets sights on PhIIb after COPD drug comes through early trial". FierceBiotech.
  3. ↑ Turner MJ, Matthes E, Billet A, Ferguson AJ, Thomas DY, Randell SH, et al. (January 2016). "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. doi: 10.1152/ajplung.00324.2015 . PMID   26545902.
  4. ↑ EP 1165558,Oxford, Alexander William&Jack, David,"Derivatives of pyrimido[6,1-a]isoquinolin-4-one",published 2002-01-02, assigned to Verona Pharma plc
  5. ↑ Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP (August 2006). "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. doi:10.1124/jpet.105.099192. PMID   16682455. S2CID   15490792.
  6. 1 2 3 4 5 "Proposed Acquisition of Rhinopharma" (PDF). Isis Resources plc. 23 August 2006. Archived from the original (PDF) on 2016-03-02.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.