| Revision as of 13:08, 8 March 2011 editYobot (talk | contribs)Bots4,733,870 editsm WP:CHECKWIKI error fixes + general fixes using AWB (7630)← Previous edit |
Latest revision as of 15:10, 24 January 2024 edit undoMaxim Masiutin (talk | contribs)Extended confirmed users, IP block exemptions, Pending changes reviewers31,058 edits Used lowercase "cite" template everywhere for consistency. Added the cs1 style template to denote Vancouver ("vanc") citation style, because references contain "vauthors" attribute to specify the list of authors. |
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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{cs1 config|name-list-style=vanc}} |
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| IUPAC_name = (3a''S'',4''R'',7''S'',9''R'',10''R'',11''R'',13''R'',15''R'',15a''R'')-1-butyl]-4-ethyl-7-fluorooctahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-{oxy}-2''H''-Oxacyclotetradecinooxazole-2,6,8,14(1''H'',7''H'',9''H'')-tetrone |
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{{Drugbox |
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| synonyms = CEM-101; OP-1068 |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 417774847 |
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| IUPAC_name = (3a''S'',4''R'',7''S'',9''R'',10''R'',11''R'',13''R'',15''R'',15a''R'')-1-butyl]-4-ethyl-7-fluorooctahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-10-{oxy}-2''H''-Oxacyclotetradecinooxazole-2,6,8,14(1''H'',7''H'',9''H'')-tetrone |
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| image = Solithromycin.svg |
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| image = Solithromycin.svg |
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| width = 250 |
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| width = 250 |
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<!--Clinical data--> |
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| ATC_prefix = none |
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| tradename = Solithera |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| legal_status = Under FDA and EMA review for approval |
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| routes_of_administration = Oral, intravenous |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 760981-83-7 |
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| CAS_number = 760981-83-7 |
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| ATC_prefix = J01 |
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| ATC_suffix = FA16 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = 9U1ETH79CK |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 1240704 |
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| synonyms = CEM-101; OP-1068 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 25056854 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| DrugBank = DB09308 |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG = D09965 |
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<!--Chemical data--> |
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| C=43 | H=65 | F=1 | N=6 | O=10 |
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| C=43 | H=65 | F=1 | N=6 | O=10 |
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| smiles = CC12(((C(=O)(C(((C(=O)(C(=O)O1)(C)F)C)O3((C(O3)C)N(C)C)O)(C)OC)C)C)N(C(=O)O2)CCCCn4cc(nn4)c5cccc(c5)N)C |
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| molecular_weight = 845.01 g/mol |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| legal_status = ] |
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| StdInChI = 1S/C43H65FN6O10/c1-12-32-43(8)35(50(40(55)60-43)19-14-13-18-49-23-30(46-47-49)28-16-15-17-29(45)21-28)26(4)33(51)24(2)22-41(6,56-11)37(27(5)36(53)42(7,44)39(54)58-32)59-38-34(52)31(48(9)10)20-25(3)57-38/h15-17,21,23-27,31-32,34-35,37-38,52H,12-14,18-20,22,45H2,1-11H3/t24-,25-,26+,27+,31+,32-,34-,35-,37-,38+,41-,42+,43-/m1/s1 |
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| routes_of_administration = oral, intravenous |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = IXXFZUPTQVDPPK-ZAWHAJPISA-N |
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}} |
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'''Solithromycin''' (formerly known as '''CEM-101''' and OP-1068) is a novel ] ] undergoing research for the treatment of ] (CAP)<ref name="pmid15117934">{{cite journal |
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'''Solithromycin''' (trade name '''Solithera''') is a ] ] undergoing clinical development for the treatment of ]<ref name="pmid15117934">{{cite journal | vauthors = Reinert RR | title = Clinical efficacy of ketolides in the treatment of respiratory tract infections | journal = The Journal of Antimicrobial Chemotherapy | volume = 53 | issue = 6 | pages = 918–927 | date = June 2004 | pmid = 15117934 | doi = 10.1093/jac/dkh169 | doi-access = free }}</ref> and other infections.<ref>{{cite web | title = Solithromycin | work = Cempra | url = http://www.cempra.com/research/antibacterials/ | archive-url = https://web.archive.org/web/20120318061805/http://www.cempra.com/research/antibacterials/| archive-date = 18 March 2012 }}</ref> |
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|author=Reinert RR |
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|title=Clinical efficacy of ketolides in the treatment of respiratory tract infections |
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|journal=The Journal of Antimicrobial Chemotherapy |
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|volume=53 |
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|issue=6 |
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|pages=918–27 |
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|year=2004 |
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|month=June |
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|pmid=15117934 |
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|doi=10.1093/jac/dkh169 |
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|url= |
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|accessdate=2009-06-21 |
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}}</ref> and other infections<ref>http://www.cempra.com/research/antibacterials/</ref>. Solithromycin exhibits excellent ] activity against a broad spectrum of ] ] ]s<ref name="pmid2017690">{{cite journal |
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|author=Woolsey LN, Castaneira M, Jones RN. |
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|title=CEM-101 activity against Gram-positive organisms |
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|journal=Antimicrobial Agents and Chemotherapy |
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|volume=54 |
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|issue=5 |
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|pages=2182–2187 |
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|year=2010 |
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|month=May |
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|pmid=2017690 |
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|doi=10.1128/AAC.01662-09 |
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|url= |
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|accessdate=2011-02-28 |
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}}</ref><ref name="pmid20211548">{{cite journal |
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|author=Farrell DJ, Sader HS, Castanheira M, Biedenbach DJ, Rhomberg PR, Jones RN. |
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|title=Antimicrobial characterization of CEM-101 activity against respiratory tract pathogens including multidrug-resistant pneumococcal serogroup 19A isolates |
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|journal=International Journal of Antimicrobial Agents |
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|volume=35 |
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|issue=6 |
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|pages=537–543 |
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|year=2010 |
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|month=June |
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|pmid=20211548 |
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|doi=10.1016/j.ijantimicag.2010.01.026 |
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|accessdate=2011-02-28 |
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}}</ref>, including macrolide-resistant strains<ref name="pmid19884376">{{cite journal |
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|author=McGhee P, Clark C, Kosowska-Shick K, Nagai K, Dewasse B, Beachel L, Appelbaum PC. |
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|title=In Vitro Activity of Solithromycin against ''Streptococcus pneumoniae'' and ''Streptococcus pyogenes'' with Defined Macrolide Resistance Mechanisms |
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|journal=Antimicrobial Agents and Chemotherapy |
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|volume=54 |
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|issue=1 |
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|pages=230–238 |
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|year=2010 |
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|month=January |
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|pmid=19884376 |
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|doi=10.1128/AAC.01123-09 |
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|url= |
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|accessdate=2011-02-28 |
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}}</ref>. Solithromycin has activity against a wide variety of pathogens<ref>{{cite journal | doi = 10.1016/j.diagmicrobio.2009.10.013 | author = Putnam, Shannon D.; Castanheira, Mariana; Moet, Gary J.; Farrell, David J.; Jones, Ronald N. | title = CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria | journal = Diagnostic Microbiology and Infectious Disease | year = 2010 | volume = 66 | issue = 4 | pages = 393–401 | pmid = 20022192}}</ref><ref>{{Cite journal | doi = 10.1016/j.ijantimicag.2010.08.021 | author = Putnam, Shannon D.; Sader, Helio S.; Farrell, David J.; Biedenbach, Douglas J.; Castanheira, Mariana | title = Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci | journal = International Journal of Antimicrobial Agents | year = 2011 | volume = 37 | issue = 1 | pages = 39–45 | pmid = 21075602}}</ref> and further research is being conducted for other ]s. |
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Solithromycin exhibits excellent '']'' activity against a broad spectrum of ] ] ]s,<ref name="pmid2017690">{{cite journal | vauthors = Woosley LN, Castanheira M, Jones RN | title = CEM-101 activity against Gram-positive organisms | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 5 | pages = 2182–2187 | date = May 2010 | pmid = 20176910 | pmc = 2863667 | doi = 10.1128/AAC.01662-09 | author-link2 = Mariana Castanheira }}</ref><ref name="pmid20211548">{{cite journal | vauthors = Farrell DJ, Sader HS, Castanheira M, Biedenbach DJ, Rhomberg PR, Jones RN | title = Antimicrobial characterisation of CEM-101 activity against respiratory tract pathogens, including multidrug-resistant pneumococcal serogroup 19A isolates | journal = International Journal of Antimicrobial Agents | volume = 35 | issue = 6 | pages = 537–543 | date = June 2010 | pmid = 20211548 | doi = 10.1016/j.ijantimicag.2010.01.026 }}</ref> including macrolide-resistant strains.<ref name="pmid19884376">{{cite journal | vauthors = McGhee P, Clark C, Kosowska-Shick KM, Nagai K, Dewasse B, Beachel L, Appelbaum PC | title = In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 1 | pages = 230–238 | date = January 2010 | pmid = 19884376 | pmc = 2798494 | doi = 10.1128/AAC.01123-09 }}</ref> Solithromycin has activity against most common respiratory Gram-positive and fastidious Gram-negative pathogens,<ref>{{cite journal | vauthors = Putnam SD, Castanheira M, Moet GJ, Farrell DJ, Jones RN | title = CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria | journal = Diagnostic Microbiology and Infectious Disease | volume = 66 | issue = 4 | pages = 393–401 | date = April 2010 | pmid = 20022192 | doi = 10.1016/j.diagmicrobio.2009.10.013 }}</ref><ref>{{cite journal | vauthors = Putnam SD, Sader HS, Farrell DJ, Biedenbach DJ, Castanheira M | title = Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci | journal = International Journal of Antimicrobial Agents | volume = 37 | issue = 1 | pages = 39–45 | date = January 2011 | pmid = 21075602 | doi = 10.1016/j.ijantimicag.2010.08.021 }}</ref> and is being evaluated for its utility in treating ]. |
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] studies have shown that solithromycin, a '''fluoroketolide''', has a third region of interactions with the bacterial ribosome<ref>{{cite journal | doi = 10.1128/AAC.00860-10 | author = Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, Mankin AS. | title = Binding and Action of CEM-101, a New Fluoroketolide Antibiotic That Inhibits Protein Synthesis| journal = Antimicrobial Agents and Chemotherapy| year = 2010 | volume = 54 | issue = 12 | pages = 4961–4970| pmid = 20855725}}</ref>, as compared with two binding sites for other ]s. |
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==Pre-clinical studies== |
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The only currently marketed ], ], suffers from rare, but serious side effects. Recent studies<ref>{{cite journal | doi = 10.1128/AAC.00840-10| author = Bertrand D, Bertrand S, Neveu E, Fernandes P. | title = Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors| journal = Antimicrobial Agents and Chemotherapy| year = 2010 | volume = 54 | issue = 12 | pages = 599-5402| pmid = 20855733}}</ref> have shown this to be likely due to the presence of the ]-] group of the telithromycin side chain interacting with ]s. Since solithromycin lacks this chemical moeity, it is not expected to cause the adverse events seen with Ketek (telithromycin). |
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An '']'' pre-clinical study performed by Jeffrey Keelan done in sheep may provide a prophylactic approach for intrauterine infections during pregnancy. This study was carried out by administering solithromycin to pregnant sheep, resulting in effective concentrations greater than 30 ng/ml in the fetal plasma, maternal plasma and amniotic fluid. A single maternal dose maintained these concentrations for over 12 hours.<ref>{{cite journal | vauthors = Keelan JA, Kemp MW, Payne MS, Johnson D, Stock SJ, Saito M, Fernandes P, Newnham JP | display-authors = 6 | title = Maternal administration of solithromycin, a new, potent, broad-spectrum fluoroketolide antibiotic, achieves fetal and intra-amniotic antimicrobial protection in a pregnant sheep model | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 1 | pages = 447–454 | date = 4 November 2013 | pmid = 24189250 | pmc = 3910757 | doi = 10.1128/AAC.01743-13 }}</ref> |
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==References== |
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==Clinical trials== |
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*May 2011: solithromycin is in a Phase 2 clinical trial for serious ] and in a Phase 1 clinical trial with an intravenous formulation.<ref name=May2011>{{cite news |url=http://www.prnewswire.com/news-releases/intravenous-iv-administration-of-cempra-pharmaceuticals-solithromycin-cem-101-demonstrates-excellent-systemic-tolerability-in-a-phase-1-clinical-trial-121433699.html |title=Intravenous (IV) Administration of Cempra Pharmaceutical's Solithromycin (CEM-101) Demonstrates Excellent Systemic Tolerability in a Phase 1 Clinical Trial |date=7 May 2011 }}</ref> |
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{{Reflist}} |
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*September 2011: solithromycin demonstrated comparable efficacy to levofloxacin with reduced adverse events in Phase 2 trial in people with community-acquired pneumonia<ref>{{cite news |url=http://www.medcitynews.com/2011/09/cempra-antibiotic-compound-as-effective-safer-than-levofloxacin/?edition=pharmaceuticals |title=Cempra antibiotic compound as effective, safer than levofloxacin |date=15 Sep 2011 }}</ref> |
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*January 2015: in a Phase 3 clinical trial for community-acquired bacterial pneumonia, solithromycin administered orally demonstrated statistical non-inferiority to the fluoroquinolone ].<ref>http://investor.cempra.com/releasedetail.cfm?ReleaseID=889300. 4 Jan 2015 {{Webarchive|url=https://web.archive.org/web/20150325011851/http://investor.cempra.com/releasedetail.cfm?ReleaseID=889300 |date=25 March 2015 }}</ref> |
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*July 2015: patient enrollment for the second Phase 3 clinical trial (Solitaire IV) for community-acquired bacterial pneumonia was completed with results expected in Q4 2015.<ref>http://investor.cempra.com/releasedetail.cfm?ReleaseID=920866. 7 July 2015 {{Webarchive|url=https://web.archive.org/web/20150908205343/http://investor.cempra.com/releasedetail.cfm?ReleaseID=920866 |date=8 September 2015 }}</ref> |
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*Oct 2015: IV to oral solithromycin demonstrated statistical non-inferiority to IV to oral moxifloxacin in adults with community-acquired bacterial pneumonia.<ref>{{cite web |url=http://investor.cempra.com/releasedetail.cfm?ReleaseID=936994 |title=Cempra Announces Positive Topline Phase 3 Clinical Results for Intravenous Solithromycin in the Treatment of Community-Acquired Bacterial Pneumonia (NASDAQ:CEMP) |access-date=2016-03-03 |archive-url=https://web.archive.org/web/20160105072945/http://investor.cempra.com/releasedetail.cfm?ReleaseID=936994 |archive-date=2016-01-05 |url-status=dead }}</ref> |
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*July 2016: Cempra announced FDA acceptance of IV and oral formulations of Solithera (solithromycin) ] for the treatment of community-acquired bacterial pneumonia.<ref>{{cite web |url=http://investor.cempra.com/releasedetail.cfm?ReleaseID=978096 |title=Cempra Announces FDA Acceptance of Solithera™ New Drug Applications in the Treatment of Community-Acquired Bacterial Pneumonia (NASDAQ:CEMP) |access-date=2016-07-09 |archive-url=https://web.archive.org/web/20160709221252/http://investor.cempra.com/releasedetail.cfm?ReleaseID=978096 |archive-date=2016-07-09 |url-status=dead }}</ref> |
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==Further reading== |
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== Structure == |
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] studies have shown solithromycin, the first fluoroketolide in clinical development, has a third region of interactions with the bacterial ribosome,<ref>{{cite journal | vauthors = Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, Mankin AS | title = Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 12 | pages = 4961–4970 | date = December 2010 | pmid = 20855725 | pmc = 2981243 | doi = 10.1128/AAC.00860-10 }}</ref> as compared with two binding sites for other ]s. |
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The only previously marketed ], ], suffers from rare but serious ]s. Recent studies<ref>{{cite journal | vauthors = Bertrand D, Bertrand S, Neveu E, Fernandes P | title = Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 12 | pages = 5399–5402 | date = December 2010 | pmid = 20855733 | pmc = 2981250 | doi = 10.1128/AAC.00840-10 }}</ref> have shown this to be likely due to the presence of the ]-] group of the telithromycin side chain acting as an antagonist towards various ]s. Solithromycin differs from telithromycin because the side chain does not significantly antagonize nicotinic acetylcholine receptors.<ref>{{cite journal | vauthors = Fernandes P, Martens E, Bertrand D, Pereira D | title = The solithromycin journey-It is all in the chemistry | journal = Bioorganic & Medicinal Chemistry | volume = 24 | issue = 24 | pages = 6420–6428 | date = December 2016 | pmid = 27595539 | doi = 10.1016/j.bmc.2016.08.035 | doi-access = free }}</ref> Instead of the pyridine-imidazole group used on telithromycin, this molecule has a triazole-phenylamine moiety.{{cn|date=March 2023}} |
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==Mechanism of action== |
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Solithromycin inhibits bacterial translation by binding to the ], preventing the offending bacteria from synthesizing proteins.<ref name=Owens>{{cite journal | vauthors = Owens B | title = Solithromycin rejection chills antibiotic sector | journal = Nature Biotechnology | volume = 35 | issue = 3 | pages = 187–188 | date = March 2017 | pmid = 28267725 | doi = 10.1038/nbt0317-187 | s2cid = 3648650 }}</ref> |
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==Side effects== |
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During a clinical study some patients presented with elevated liver enzyme which may or may not be indicative of ]. This prompted the FDA Antimicrobial Drugs Advisory Committee to vote that the ] has not been adequately characterized and that further studies need to be conducted. To this extent, the ] requests a 9,000 patient safety trial as well as restricting the drug. |
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==Development== |
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In 2008, ]s for solithromycin capsules and an intravenous formulation were submitted. From studies of ], safety, and efficacy several issues were found. There is variable absorption which can result in subtherapeutic drug concentrations and even therapy failure. Additionally, there are significant drug-drug interactions affecting solithromycin concentrations as well the concentrations of the offending drugs. There is also a narrow therapeutic margin which can make this drug challenging to dose.<ref>{{cite web|title=FDA Briefing Document Solithromycin Oral Capsule and Injection Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC)|url=https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm527690.pdf|website=www.fda.gov|access-date=31 October 2017}}</ref> |
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==Commercial aspects== |
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Cempra's general plan is to develop solithromycin develop products through late stage clinical trials and sell them to their hospital based sales force or through partnerships, which would need negotiations with larger pharmaceutical companies.<ref name=Cempra >{{cite web|title=Cempra Annual Report|url=http://investor.cempra.com/secfiling.cfm?filingID=1193125-13-96011|website=investor.cempra.com|language=en|access-date=2017-10-30|archive-url=https://web.archive.org/web/20151005211456/http://investor.cempra.com/secfiling.cfm?filingID=1193125-13-96011|archive-date=2015-10-05|url-status=dead}}</ref> There are several manufacturing plants used such as Wockhardt Limited and Hospira Incorporated manufacturing facilities as well as Uquifa Laboratories, an alternative GMP facility.<ref>{{cite web |title=Cempra Receives Complete Response Letter From FDA For Solithromycin NDAs (NASDAQ:CEMP) |url=http://investor.cempra.com/releasedetail.cfm?ReleaseID=1005708 |website=investor.cempra.com |language=en |access-date=2017-10-31 |archive-url=https://web.archive.org/web/20170704154336/http://investor.cempra.com/releasedetail.cfm?ReleaseID=1005708 |archive-date=2017-07-04 |url-status=dead }}</ref> |
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==Intellectual property== |
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Due to the fact that bringing new products to the market takes a significant investment of time and money, companies place considerable importance on patent protection for new products. Solithromycin is a new chemical entity from the ] library of compounds that were licensed by ]. It is covered by a series of patents and patent applications which claim the composition of matter of solithromycin.<ref>{{cite web|title=Cempra, Inc. - Annual Report|url=http://investor.cempra.com/secfiling.cfm?filingID=1193125-13-96011|website=investor.cempra.com|language=en|access-date=2017-10-30|archive-url=https://web.archive.org/web/20151005211456/http://investor.cempra.com/secfiling.cfm?filingID=1193125-13-96011|archive-date=2015-10-05|url-status=dead}}</ref> There are also patents surrounding the synthesis and purification of this substance. For example, patent EP3190122 A1 presents a novel, efficient route of synthesis that bypasses the need for chromatographic purification which saves time.<ref>{{cite patent |title=A novel synthetic pathway towards solithromycin and purification thereof |url=https://www.google.com/patents/EP3190122A1?cl=en |pubdate=2017-07-12 | country = EP | number = 3190122}}</ref> |
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== References == |
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{{Reflist}} |
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{{Macrolides, lincosamides and streptogramins}} |
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{{antibiotic-stub}} |
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