Orotomides are a class of experimental antifungals. They were discovered in 2015 by British scientists at the pharmaceutical company F2G Ltd.[1] while searching for a new drug for Aspergillus infection. The discovery was formally announced at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) 55th meeting during 17-21 September 2015 at San Diego, California,[2] and published the next year in the Proceedings of the National Academy of Sciences.[3] It was found to be effective against most important human fungal infections including those with Aspergillus, Lemontospora (Scedosporium) prolificans, Fusarium, Penicillium spp., and Taloromyces. The most promising drug candidate is designated F901318, chemical name 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl)piperazin-1-yl]-phenyl}-2-oxo-acetamide. F901318 has been named Olorofim.[4]
Chemical structure of the orotomide F901318
Unlike other antifungal drugs, the orotomides act differently by stopping pyrimidine biosynthesis in fungal cells. They cause reversible inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme that catalyses dihydroorotate to orotate. This inhibition in turn block the growth of hyphae. This unique action makes it more effective than other antifungal drugs.[5] Originally named the F3 series, the name was changed to orotomides, combining the names of the compound (dihydroorotate) they acted upon with the chemical group (α-ketoamide) which they belong to.[3]
The European Medicines Agency (EMA) Committee for Orphan Medicinal Products granted orphan designation to F2G for F901318 for the treatment of scedosporiosis on 29 August 2016,[6] and for invasive aspergillosis on 14 October 2016.[7] As of May 2017, F901318 is in late phase 1 clinical trials.[8] It was shown to be useful for acute sinopulmonary aspergillosis caused by Aspergillus flavus.[9]
Referencesedit
^Birch, Michael (19 September 2015). "The antifungal activity of F901318, a new antifungal agent from the novel orotomide class". www.asm.org. American Society For Microbiology. Retrieved 8 October 2017.
^Oliver, J.; Law, D.; Sibley, G.; Kennedy, A.; Birch, M. "F901318, a Novel Antifungal Agent from the Orotomide Class: Discovery and Mechanism of Action". Aspergillus & Aspergillosis Website. Retrieved 9 October 2017.
^ abOliver, Jason D.; Sibley, Graham E. M.; Beckmann, Nicola; Dobb, Katharine S.; Slater, Martin J.; McEntee, Laura; du Pré, Saskia; Livermore, Joanne; et al. (2016). "F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase". Proceedings of the National Academy of Sciences. 113 (45): 12809–12814. Bibcode:2016PNAS..11312809O. doi:10.1073/pnas.1608304113. PMC5111691. PMID 27791100.
^Wiederhold, Nathan P.; Najvar, Laura K.; Jaramillo, Rosie; Olivo, Marcos; Birch, Michael; Law, Derek; Rex, John H.; Catano, Gabriel; Patterson, Thomas F. (September 2018). "The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis". Antimicrobial Agents and Chemotherapy. 62 (9). doi:10.1128/AAC.00999-18. ISSN 1098-6596. PMC6125497. PMID 29941638.
^Hope, William W.; McEntee, Laura; Livermore, Joanne; Whalley, Sarah; Johnson, Adam; Farrington, Nicola; Kolamunnage-Dona, Ruwanthi; Schwartz, Julie; et al. (2017). "Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease". mBio. 8 (4). e01157-17. doi:10.1128/mBio.01157-17. PMC5565967. PMID 28830945.
^"EU/3/16/1713 Orphan designation". European Medicines Agency. Retrieved 9 October 2017.
^"EU/3/16/1738 Orphan designation". European Medicines Agency. Retrieved 9 October 2017.
^"Drug Profile F 901318". Adis Insight. Springer International Publishing AG. Retrieved 9 October 2017.
^Negri, Clara E; Johnson, Adam; McEntee, Laura; Box, Helen; Whalley, Sarah; Schwartz, Julie A; Ramos-Martín, V; Livermore, Joanne; et al. (April 2018). "Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus". The Journal of Infectious Diseases. 217 (7): 1118–1127. doi:10.1093/infdis/jix479. PMC5909626. PMID 28968675.
February 16, 2024
orotomide, class, experimental, antifungals, they, were, discovered, 2015, british, scientists, pharmaceutical, company, while, searching, drug, aspergillus, infection, discovery, formally, announced, interscience, conference, antimicrobial, agents, chemothera. Orotomides are a class of experimental antifungals They were discovered in 2015 by British scientists at the pharmaceutical company F2G Ltd 1 while searching for a new drug for Aspergillus infection The discovery was formally announced at the Interscience Conference on Antimicrobial Agents and Chemotherapy ICAAC 55th meeting during 17 21 September 2015 at San Diego California 2 and published the next year in the Proceedings of the National Academy of Sciences 3 It was found to be effective against most important human fungal infections including those with Aspergillus Lemontospora Scedosporium prolificans Fusarium Penicillium spp and Taloromyces The most promising drug candidate is designated F901318 chemical name 2 1 5 dimethyl 3 phenyl 1H pyrrol 2 yl N 4 4 5 fluoro pyrimidin 2 yl piperazin 1 yl phenyl 2 oxo acetamide F901318 has been named Olorofim 4 Chemical structure of the orotomide F901318Unlike other antifungal drugs the orotomides act differently by stopping pyrimidine biosynthesis in fungal cells They cause reversible inhibition of dihydroorotate dehydrogenase DHODH an enzyme that catalyses dihydroorotate to orotate This inhibition in turn block the growth of hyphae This unique action makes it more effective than other antifungal drugs 5 Originally named the F3 series the name was changed to orotomides combining the names of the compound dihydroorotate they acted upon with the chemical group a ketoamide which they belong to 3 The European Medicines Agency EMA Committee for Orphan Medicinal Products granted orphan designation to F2G for F901318 for the treatment of scedosporiosis on 29 August 2016 6 and for invasive aspergillosis on 14 October 2016 7 As of May 2017 F901318 is in late phase 1 clinical trials 8 It was shown to be useful for acute sinopulmonary aspergillosis caused by Aspergillus flavus 9 References edit Birch Michael 19 September 2015 The antifungal activity of F901318 a new antifungal agent from the novel orotomide class www asm org American Society For Microbiology Retrieved 8 October 2017 Oliver J Law D Sibley G Kennedy A Birch M F901318 a Novel Antifungal Agent from the Orotomide Class Discovery and Mechanism of Action Aspergillus amp Aspergillosis Website Retrieved 9 October 2017 a b Oliver Jason D Sibley Graham E M Beckmann Nicola Dobb Katharine S Slater Martin J McEntee Laura du Pre Saskia Livermore Joanne et al 2016 F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase Proceedings of the National Academy of Sciences 113 45 12809 12814 Bibcode 2016PNAS 11312809O doi 10 1073 pnas 1608304113 PMC 5111691 PMID 27791100 Wiederhold Nathan P Najvar Laura K Jaramillo Rosie Olivo Marcos Birch Michael Law Derek Rex John H Catano Gabriel Patterson Thomas F September 2018 The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis Antimicrobial Agents and Chemotherapy 62 9 doi 10 1128 AAC 00999 18 ISSN 1098 6596 PMC 6125497 PMID 29941638 Hope William W McEntee Laura Livermore Joanne Whalley Sarah Johnson Adam Farrington Nicola Kolamunnage Dona Ruwanthi Schwartz Julie et al 2017 Pharmacodynamics of the Orotomides against Aspergillus fumigatus New Opportunities for Treatment of Multidrug Resistant Fungal Disease mBio 8 4 e01157 17 doi 10 1128 mBio 01157 17 PMC 5565967 PMID 28830945 EU 3 16 1713 Orphan designation European Medicines Agency Retrieved 9 October 2017 EU 3 16 1738 Orphan designation European Medicines Agency Retrieved 9 October 2017 Drug Profile F 901318 Adis Insight Springer International Publishing AG Retrieved 9 October 2017 Negri Clara E Johnson Adam McEntee Laura Box Helen Whalley Sarah Schwartz Julie A Ramos Martin V Livermore Joanne et al April 2018 Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus The Journal of Infectious Diseases 217 7 1118 1127 doi 10 1093 infdis jix479 PMC 5909626 PMID 28968675 Retrieved from https en wikipedia org w index php title Orotomide amp oldid 1195506334, wikipedia, wiki, book, books, library,
