| 词条 | Brilacidin |
| 释义 |
| IUPAC_name = N,N'-bis[3[5-(carbamimidoylamino)pentanoyl]amino2-[(3R)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)phenyl]pyrimidine-4,6-dicarboxamide[1] | image = Brilacidin.svg | width = 300px | alt = | image2 = | width2 = | alt2 = | caption = | tradename = None as of July 2012[1] | Drugs.com = | MedlinePlus = | licence_EU = | licence_US = | DailyMedID = | pregnancy_AU = | pregnancy_US = | pregnancy_category= | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | dependency_liability = | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number = 1224095-98-0 | ATCvet = | ATC_prefix = none | ATC_suffix = | ATC_supplemental = | ChEMBL = 2219413 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = I1679X069H | PubChem = 25023695 | PubChemSubstance = | IUPHAR_ligand = | DrugBank = | ChemSpiderID = 28651526 | KEGG = D10414 | ChEBI = | synonyms = | C=40 | H=50 | F=6 | N=14 | O=6 | molecular_weight = 936.9 g/mol | SMILES = C1CNC[C@@H]1OC2=C(C=C(C=C2NC(=O)C3=CC(=NC=N3)C(=O)NC4=CC(=CC(=C4O[C@@H]5CCNC5)NC(=O)CCCCNC(=N)N)C(F)(F)F)C(F)(F)F)NC(=O)CCCCNC(=N)N | StdInChI = 1S/C40H50F6N14O6/c41-39(42,43)21-13-25(57-31(61)5-1-3-9-53-37(47)48)33(65-23-7-11-51-18-23)27(15-21)59-35(63)29-17-30(56-20-55-29)36(64)60-28-16-22(40(44,45)46)14-26(34(28)66-24-8-12-52-19-24)58-32(62)6-2-4-10-54-38(49)50/h13-17,20,23-24,51-52H,1-12,18-19H2,(H,57,61)(H,58,62)(H,59,63)(H,60,64)(H4,47,48,53)(H4,49,50,54)/t23-,24-/m1/s1 | StdInChIKey = QPDYBCZNGUJZDK-DNQXCXABSA-N | density = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | specific_rotation = | sec_combustion = }} Brilacidin (formerly PMX-30063[2]), an investigational new drug (IND), is a polymer-based antibiotic currently in human clinical trials, and represents a new class of antibiotics called host defense protein mimetics, or HDP-mimetics, which are non-peptide synthetic small molecules modeled after host defense peptides (HDPs).[3][4][5] HDPs, also called antimicrobial peptides, some of which are defensins, are part of the innate immune response and are common to most higher forms of life.[6][7] As brilacidin is modeled after a defensin, it is also called a defensin mimetic. Brilacidin is an antibiotic that works by disrupting bacterial cell membranes, mimicking defensins that play a role in innate immunity.[8][9] Several mimics of antimicrobial peptides, both peptides and non-peptides, have been studied, but none have overcome difficulties to reach the market. Structure and actionBrilacidin, a non-peptide chemical mimic, is an arylamide foldamer designed to replicate the amphiphilic properties of antimicrobial peptides while solving the problems encountered by peptide-based antimicrobials.[10] Brilacidin, a broad-spectrum antibiotic, has potent Gram positive activity and Gram negative coverage,[11] and is highly effective in treating the 'superbug' methicillin-resistant Staphylococcus aureus (MRSA). Brilacidin has low cytotoxicity against mammalian cells while selectively targeting bacteria, directly and rapidly disrupting their membranes, resulting in the bacteria's death. Due to this unique mechanism of action (mimicking the host's natural immune response, proven to be successful in fighting off infections over millions of years of evolution), bacterial antibiotic resistance is less likely to develop.[12][13][14][15] Potential significanceThere has not been a new drug approval from a new class of antibiotics since 1987. While six antibiotics have been approved over the last year, they are all adaptations of existing antibiotic classes.[16] None of the recently approved novel antibiotics represent entirely new classes.[17] Novel antibiotics are crucial as antibiotic resistance poses a global health risk. The World Health Organization, warning of a "post-antibiotic era" has stated that antimicrobial resistance (AMR) is a "problem so serious that it threatens the achievements of modern medicine".[18] HistoryLeveraging advanced computational bioinformatics,[19][20][21] brilacidin and other defensin mimetics[22] were first developed by University of Pennsylvania-based researchers.[23][24] Their efforts were consolidated, and officially incorporated, in 2002, under the company name PolyMedix. PolyMedix conducted pre-clinical and clinical research with brilacidin through a completed Phase 2a human clinical trial with positive results.[25] After discontinuing a clinical trial for an unrelated compound PolyMedix filed for Chapter 7 bankruptcy protection on April 1, 2013. Cellceutix acquired the PolyMedix assets and intellectual property, including the licenses and patents for brilacidin and the rest of the HDP-mimetic pipeline, from bankruptcy court which on September 4, 2013 approved Cellceutix's stalking horse bid.[26][27] Other usesCellceutix is pursuing other clinical applications of brilacidin and related anti-infective HDP-mimetic compounds, including their prophylactic use on implanted medical devices, having already entered into a material transfer agreement with a division of a large U.S. pharmaceutical company.[28] An active clinical trial, brilacidin for oral mucositis is detailed below. In pre-clinical research, a mouthwash formulation of brilacidin was well-tolerated and efficacious for oral mucositis, significantly reducing the number of days with ulcerations and significantly reducing the mucositis scores in a dose dependent manner.[29] Pre-clinical research has shown potential for brilacidin for ocular,[30][31] Otic,[32] and diabetic foot ulcers.[33] Clinical trialsPolyMedix advanced brilacidin through early stage human clinical trials to a completed Phase 2a proof-of-concept clinical trial. Since acquisition, brilacidin has to date completed a Phase 2b clinical trial with positive results. Results, as detailed below, showed brilacidin compared favorably with Daptomycin, though administered in a single-dose as compared to Daptomycin's 7-day dosing regimen. Discussions presently are underway between Cellceutix and the FDA to begin a pivotal Phase 3 trial for ABSSSI. Plans and trial design for the Phase 3 clinical trail(s) are expected be made public after the post-P2b clinical trial with the FDA expected in June 2015 Brilacidin was granted the Qualified Infectious Disease Product (QIDP) designation by the FDA under the Generating Antibiotic Incentives Now Act of 2011 (GAIN Act).[34] Receiving QIDP designation means that brilacidin is now eligible for additional FDA incentives in the approval and marketing pathway, including fast track designation and priority review for development and a five-year extension of market exclusivity.[35] Phase 2a clinical trial – ABSSSIInitial Treatment for Acute Bacterial Skin Infections (ABSSSI) Caused by Staphylococcus aureus[36] Randomized, Dose Ranging, Active Controlled Efficacy and Safety Evaluation of PMX-30063 As Initial Treatment for Acute Bacterial Skin and Skin Structure Infections (ABSSSI) Caused by Staphylococcus aureusThe study started in October 2010 and had a primary completion date of December 2011 for final data collection for the primary outcome measure. Overall, 215 patients were randomized into either one of the three brilacidin arms or the active comparator Daptomycin arm. There were three dosing regimens for brilacidin, a low, medium and high dose administered for three days, and one dosing regimen for Daptomycin administered for seven days.[37] The clinical trial was successful, demonstrating safety and clinical efficacy for all evaluated doses of brilacidin, with three-day brilacidin cure rates of all dosing regimens comparable with seven days of Daptomycin. The results indicated the potential for a shorter brilacidin dosing regimen.[38] Shorter dosing regimens are important as they reduce the risks from Intravenous therapy complications, reduce costs such as reduced hospital stays and clinic visits, and can help reduce the emergence of antibiotic resistance through a combination of a quick bacterial kill, shorter duration of treatment,[39] and increased patient compliance. As patients may feel better before treatment is complete and discontinue treatment too early, this is a risk for their health and also the development of antibiotic resistance. A single one day dosage eliminates the risk of patient non-compliance. Phase 2b clinical trial – ABSSSIEfficacy and Safety Study of Brilacidin to Treat Serious Skin Infections[40] A Randomized, Double-Blind Study Comparing Three Dosing Regimens of Brilacidin to daptomycin in the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI)The study started February 2014 and announced completed enrollment August 19, 2014. Overall, 215 patients were randomized to one of three dosing regimens of brilacidin (single dose 0.6 mg/kg; single-dose 0.8 mg/kg; 1.2 mg/kg over 3 days) or 7 days of once daily daptomycin.[40] The Clinical Trial had positive results, indicating that single dose brilacidin was comparable to 7 days of daptomycin. The primary endpoint was clinical success in the intent-to-treat population, defined as reduction of at least 20% in area of the ABSSSI lesion, relative to baseline, when observed 48–72 hours after the first dose of study drug, and no rescue antibiotics administered. All three brilacidin treatment arms (two single-dose regimens and one three-day dose regimen) had clinical success rates comparable to the clinical success rate of the FDA-approved seven-day dosing regimen of daptomycin. All brilacidin treatment regimens were generally well tolerated. There were six serious adverse events (SAEs) reported in the study, none of which were considered related to brilacidin by the principal investigator. The results were also positive in the microbiological intent-to-treat population (MITT). This is an important population, as it consists of patients enrolled in the trial who had cultures obtained at the baseline visit that were positive for common ABSSSI pathogens. Most of these cultures grew Staphylococcus aureus, and approximately 40% of these were (MRSA). This is currently the most important bacterial pathogen in patients with ABSSSI. The P2b clinical trial results were reported for peer review by abstract and oral presentation at the 2015 European Congress of Clinical microbiology and Infectious Diseases [41][42][43] Phase 2 clinical trial – oral mucositisPhase 2 Study to Evaluate the Safety & Efficacy of Brilacidin Oral Rinse in Patients With Head and Neck Cancer[44]The brilacidin trial for oral mucositis (Briladidin-OM) has started in May 2015 and is expected to be completed in December 2017. Brilacidin-OM is an oral rinse of brilacidin in water. Approximately 60 patients who are receiving chemoradiation for head and neck cancer are randomized to receive either brilacidin-OM or the placebo three times daily for seven weeks. The study design is double blind. Various primary and secondary outcome measures will be recorded to assess efficacy of brilacidin-OM to prevent or reduce the severity of oral mucositis in patients receiving chemo-radiation.[44] The HDP-mimetic pipelineDevelopment is ongoing for numerous brilacidin analogs, selected by laboratory testing of the various HDP mimetics and defensin-mimetic compounds in the antibiotic pipeline. Pre-clinical research has been shown select brilacidin analogs effective in killing a variety of important Gram-negative pathogens (the so-called superbugs), such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Acinetobacter baumannii as well as highly multi-drug resistant ndm-1-producing K. pneumoniae.[45] An abstract update on these efforts was presented at the European Congress of Clinical Microbiology and Infectious Disease ([https://web.archive.org/web/20150426065637/http://eccmid.meetingexpert.net/ECCMID_546/StaticContainer/Welcome ECCMID]) 2015 annual conference. The footnote links to the full presentation.[46] Other HDP-Mimetic analogs have proven effective in vitro against C. albicans and other Candida species.[47] Also acquired with brilacidin and the HDP-mimetic pipeline were the rights to the related PolyCide family of compounds, polymeric formulations that function as antimicrobial agents. These compounds are similar to brilacidin in that they are also synthetic mimics of HDPs. These compounds have superior bacterial killing activity over triclosan and silver nitrate, common biocidal agents. PolyCide compounds could be used as additives to paints, plastics, textiles and other materials to create self-sterilizing products and surfaces.[48][49][50] Notes1. ^1 {{cite journal|url=http://www.ama-assn.org/resources/doc/usan/brilacidin.pdf|title=Statement on a nonproprietary name adopted by the USAN council |date=July 25, 2012|publisher=American Medical Association}} 2. ^{{cite web|url=http://files.shareholder.com/downloads/ABEA-4ITCYZ/1997024712x0x611205/FEA66C67-D02F-4FF2-B230-AA711F46ED7F/PMX-30063_Antibiotic_Fact_Sheet_Nov_2012_.pdf|title=Fact Sheet |publisher=PolyMedix }} 3. ^{{cite web |url=http://deepblue.lib.umich.edu/bitstream/handle/2027.42/84494/efp_1.pdf?sequence=1 |title=Antimicrobial Polymers: peptide-mimetic design and mechanism of action | last=Palermo| first=Edmund Francis| publisher=University of Michigan Library|date=2011 }} 4. ^{{cite web|url=http://deepblue.lib.umich.edu/bitstream/handle/2027.42/84494/efp_2.pdf?sequence=2|title=The convergence of peptide and polymer science toward novel antibiotics | last=Palermo| first=Edmund Francis| publisher=University of Michigan Library|date=2011 }} 158pages 5. ^{{cite web|url=http://openarchive.univpm.it/jspui/bitstream/123456789/304/1/Tesi.Sgolastra.pdf|title=Design and synthesis of biomimetic compounds with pharmacological activity | last=Sgolastra| first=Dr. Frederica| publisher=Universita' Politecnica Delle Marche}} 6. ^{{cite journal |last=Kuroda|first=Kenichi |author2=Caputo, Gregory |title=Antimicrobial polymers as synthetic mimics of host-defense peptides |journal=Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology |date=2013|volume=5|issue=1|pages=49–66|doi=10.1021/bk-2013-1135.ch019}} 7. ^{{cite web|url=https://www.pse.umass.edu/sites/default/files/tew/images/Tew-Acc%20Chem%20Res-2013-2977.pdf | title=Designing mimics of membrane active proteins }} Accounts of Chemical Research 8. ^{{cite web|url=http://www.biocentury.com/products/pmx-30063|title=brilacidin (formerly PMX-30063)|work=BioCentury BCIQ|accessdate=2013-09-19|publisher=BioCentury Publications}} 9. ^{{cite journal|last=Butler|first=Mark S|author2=Cooper, Matthew A|title=Antibiotics in the clinical pipeline in 2011|journal=The Journal of Antibiotics|date=18 May 2011|volume=64|issue=6|pages=413–425|doi=10.1038/ja.2011.44|pmid=21587262}} 10. ^{{cite journal|last=Pucci|first=Michael J|last2=Bush| first2=Karen|title=Investigational antimicrobial agents of 2013|journal=Clinical Microbiology Reviews|date=October 2013|volume=26|issue=4|pages=792–821|doi=10.1128/CMR.00033-13|pmid=24092856|pmc=3811234}} 11. ^{{cite web|url=http://cellceutix.com/wp-content/uploads/2014/06/ECCMID-2015-OM-poster.pdf | title=ECCMID poster: brilacidin, host defence peptide mimetic, one of a new class of immunomodulatory agents that can target multiple disease indications |publisher=Celleutix }} 12. ^{{cite journal|last=Steinstraesser|first=Lars|display-authors=etal|title=Host defense peptides as effector molecules of the innate immune response: a sledgehammer for drug resistance?|journal=Int. 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web|url=http://www.qmed.com/mpmn/article/synthetic-polymer-mimics-antimicrobial-properties-host-defense-proteins|title=Synthetic polymer mimics antimicrobial properties of host-defense proteins |publisher=Qmed }} 49. ^{{cite web|url=http://plasticsengineeringblog.com/2011/02/15/in-the-front-lines-of-germ-warfare/|title=Plastics Engineering |date=February 15, 2011 }} 50. ^{{cite press release|url=http://globenewswire.com/news-release/2012/09/05/488925/10004018/en/Data-Showing-Effectiveness-of-PolyCide-Antimicrobial-in-Surgical-Suture-Coatings-Published-in-American-Chemical-Society-Journal-Langmuir.html/#sthash.p3pPWvmS.dpbs|title=Data showing effectiveness of PolyCide antimicrobial in surgical suture coatings published in American Chemical Society Journal, Langmuir |publisher=Globe NewsWire}} References
6 : Antibiotics|Experimental drugs|Trifluoromethyl compounds|Guanidines|Pyrrolidines|Pyrimidines |
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