OSU-03012

Last updated
OSU-03012
OSU-03012.svg
Names
IUPAC name
2-Amino-N-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide
Other names
AR-12
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
UNII
  • InChI=1S/C26H19F3N4O/c27-26(28,29)24-14-23(33(32-24)20-10-8-19(9-11-20)31-25(34)15-30)18-7-12-22-17(13-18)6-5-16-3-1-2-4-21(16)22/h1-14H,15,30H2,(H,31,34)
    Key: YULUCECVQOCQFQ-UHFFFAOYSA-N
  • InChI=1/C26H19F3N4O/c27-26(28,29)24-14-23(33(32-24)20-10-8-19(9-11-20)31-25(34)15-30)18-7-12-22-17(13-18)6-5-16-3-1-2-4-21(16)22/h1-14H,15,30H2,(H,31,34)
    Key: YULUCECVQOCQFQ-UHFFFAOYAU
  • C1=CC=C2C(=C1)C=CC3=C2C=CC(=C3)C4=CC(=NN4C5=CC=C(C=C5)NC(=O)CN)C(F)(F)F
Properties
C26H19F3N4O
Molar mass 460.460 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

OSU-03012 (AR-12) is a celecoxib derivative with anticancer and anti-microbial activity. Unlike celecoxib, OSU-03012 does not inhibit COX, but inhibits several other important enzymes instead which may be useful in the treatment of some forms of cancer, [1] [2] When combined with PDE5 inhibitors such as sildenafil or tadalafil, OSU-03012 was found to show enhanced anti-tumour effects in cell culture. [3]

Contents

Antimicrobial agent

Antimicrobial activity is often not against the microbe directly (like conventional antibiotics), but rather host-directed activity that works on the cellular host to disrupt the pathogen within the cell. [16] Since the median lethal dose (LD50), in vitro , against macrophages is ~7 μM and near its effective concentration (EC50) [17] [18] formulation of the compound has been shown to enhances its activity. For example, encapsulation of OSU-03012 into biodegradable polymeric (Acetalated dextran) micro/nanoparticles significantly reduces cytotoxicity, increases drug concentration per a cell, reduces toxicity in vivo , and facilitates needle-free delivery in vivo . [19] [20]

Orphan drug designation

The European Commission has designated OSU-03012 as an orphan drug for use in combination with other drugs for treatment of two infections diseases, cryptococcosis and tularaemia. OSU-03012 received an orphan drug designation in combination with the antifungal drug fluconazole for cryptococcosis of the brain. It also received this designation for tularaemia in combination with the antibacterial drug gentamicin. [21]

Related Research Articles

<span class="mw-page-title-main">Cilastatin</span> Chemical compound

Cilastatin inhibits the human enzyme dehydropeptidase.

<span class="mw-page-title-main">Faropenem</span> Chemical compound

Faropenem is an orally active beta-lactam antibiotic belonging to the penem group. It is resistant to some forms of extended-spectrum beta-lactamase. It is available for oral use.

Cyanovirin-N (CV-N) is a protein produced by the cyanobacterium Nostoc ellipsosporum that displays virucidal activity against several viruses, including human immunodeficiency virus (HIV). A cyanobacterial protein called cyanovirin-N (CV-N) has strong anti-human immunodeficiency virus (HIV) neutralizing properties. The virucidal activity of CV-N is mediated through specific high-affinity interactions with the viral surface envelope glycoproteins gp120 and gp41, as well as to high-mannose oligosaccharides found on the HIV envelope. In addition, CV-N is active against rhinoviruses, human parainfluenza virus, respiratory syncytial virus, and enteric viruses. The virucidal activity of CV-N against influenza virus is directed towards viral haemagglutinin.

<span class="mw-page-title-main">Walter Dobrogosz</span>

Walter Dobrogosz is a professor emeritus of North Carolina State University, best known for his discovery and further research on the probiotic bacterium Lactobacillus reuteri.

<span class="mw-page-title-main">Thiocarlide</span> Chemical compound

Thiocarlide is a thiourea drug used in the treatment of tuberculosis, inhibiting synthesis of oleic acid and tuberculostearic acid.

<span class="mw-page-title-main">Aminocoumarin</span> Class of antibiotic chemical compounds

Aminocoumarin is a class of antibiotics that act by an inhibition of the DNA gyrase enzyme involved in the cell division in bacteria. They are derived from Streptomyces species, whose best-known representative – Streptomyces coelicolor – was completely sequenced in 2002. The aminocoumarin antibiotics include:

Antimicrobial pharmacodynamics is the relationship between the concentration of an antibiotic and its ability to inhibit vital processes of endo- or ectoparasites and microbial organisms. This branch of pharmacodynamics relates the concentration of an anti-infective agent to its effect, specifically to its antimicrobial effect.

<span class="mw-page-title-main">Bevirimat</span> Chemical compound

Bevirimat is an anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium claviflorum, a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition. It is not currently U.S. Food and Drug Administration (FDA) approved. It was originally developed by the pharmaceutical company Panacos and reached Phase IIb clinical trials. Myriad Genetics announced on January 21, 2009 the acquisition of all rights to bevirimat for $7M USD. On June 8, 2010 Myriad Genetics announced that it was abandoning there HIV portfolio to focus more on cancer drug development.

<span class="mw-page-title-main">Brecanavir</span> Chemical compound

Brecanavir is a protease inhibitor which has been studied for the treatment of HIV.

<span class="mw-page-title-main">Biapenem</span> Chemical compound

Biapenem (INN) is a carbapenem antibiotic. It has in vitro activity against anaerobes. 1-β-methyl-carbapenem antibiotic. Approved in Japan in 2001.

<span class="mw-page-title-main">Tigemonam</span> Chemical compound

Tigemonam is a monobactam antibiotic.

<span class="mw-page-title-main">5-Dehydroepisterol</span> Chemical compound

5-Dehydroepisterol is a sterol and an intermediate in steroid biosynthesis, particularly synthesis of brassinosteroids. It is formed from episterol through action of ERG3, the C-5 sterol desaturase in the yeast and is then converted into 24-methylenecholesterol by 7-dehydrocholesterol reductase.

<span class="mw-page-title-main">Phanquinone</span> Chemical compound

Phanquinone is an organic compound. It is a yellowish solid derived by oxidation of 4,7-phenanthroline.

<span class="mw-page-title-main">Radezolid</span> Chemical compound

Radezolid is a novel oxazolidinone antibiotic being developed by Melinta Therapeutics, Inc. for the treatment of bacterial acne.

<span class="mw-page-title-main">Nemonoxacin</span> Chemical compound

Nemonoxacin is a non-fluorinated quinolone antibiotic undergoing clinical trials. It has the same mechanism of action as fluouroquinolones; it inhibits DNA gyrase, preventing DNA synthesis, gene duplication, and cell division. At the end of 2016, it had reached market in Taiwan, Russia, the Commonwealth Independent States, Turkey, mainland China, and Latin America under the brand name Taigexyn. Nemonoxacin has completed phase 2 trials in the US and has moved on to phase 3 trials. The U.S. Food and Drug Administration (FDA) has granted nemonoxacin qualified infectious disease product (QIDP) and fast track designations for community-acquired bacterial pneumonia (CAP) and acute bacterial skin and skin-structure infections (ABSSSI).

<span class="mw-page-title-main">Acetalated dextran</span> Chemical compound

Acetalated dextran is a biodegradable polymer based on dextran that has acetal modified hydroxyl groups. After synthesis, the hydrophilic polysaccharide dextran is rendered insoluble in water, but soluble in organic solvents. This allows it to be processed in the same manner as many polyesters, like poly(lactic-co-glycolic acid), through processes like solvent evaporation and emulsion. Acetalated dextran is structurally different from acetylated dextran.

Host-directed therapeutics, also called host targeted therapeutics, act via a host-mediated response to pathogens rather than acting directly on the pathogen, like traditional antibiotics. They can change the local environment in which the pathogen exists to make it less favorable for the pathogen to live and/or grow. With these therapies, pathogen killing, e.g.bactericidal effects, will likely only occur when it is co-delivered with a traditional agent that acts directly on the pathogen, such as an antibiotic, antifungal, or antiparasitic agent. Several antiviral agents are host-directed therapeutics, and simply slow the virus progression rather than kill the virus. Host-directed therapeutics may limit pathogen proliferation, e.g., have bacteriostatic effects. Certain agents also have the ability to reduce bacterial load by enhancing host cell responses even in the absence of traditional antimicrobial agents.

Kristy M. Ainslie is a Fred Eshelman Distinguished Professor in pharmaceutical science at University of North Carolina at Chapel Hill in the Eshelman School of Pharmacy and chair of the Division of Pharmacoengineering and Molecular Pharmaceutics. She is also joint in the UNC School of Medicine Department of Microbiology and Immunology and affiliated faculty in the UNC/NC State joint Biomedical Engineering department. Additionally, she is part of UNC's Biological and Biomedical Sciences Program (BBSP).

<span class="mw-page-title-main">Karen Bush</span> American biochemist

Karen Bush is an American biochemist. She is a professor of Practice in Biology Emerita at Indiana University Bloomington and served as the interim director of the Biotechnology program from 2019-2022. Bush conducts research focusing on the activity of novel antimicrobial agents against Gram-negative bacteria and bacterial resistance mechanisms to beta-lactam antibiotics.

Karen Joy Shaw is an American microbiologist and discoverer of novel antifungal and antibacterial compounds. She is best known for her work on aminoglycoside resistance in bacteria as well as leading drug discovery research teams. As Senior Vice President of Biology at Trius Therapeutics, Inc. her work was critical to the development of the oxazolidinone antibiotic tedizolid phosphate (Sivextro) as well as the discovery of the TriBE inhibitors, a novel class of DNA gyrase/Topoisomerase IV antibacterial agents that target both Gram-positive and Gram-negative organisms.[2] As Chief Scientific Officer at Amplyx Pharmaceuticals, Shaw was responsible for the preclinical development of the novel antifungal fosmanogepix, a first-in-class broad-spectrum antifungal prodrug that is currently in Phase 2 clinical development for the treatment of invasive fungal infections. She also discovered APX2039, a unique Gwt1 inhibitor that is in preclinical development for the treatment of cryptococcal meningitis.

References

  1. ↑ Booth, L; Cruickshanks, N; Ridder, T; Chen, CS; Grant, S; Dent, P (Dec 2012). "OSU-03012 interacts with lapatinib to kill brain cancer cells". Cancer Biology and Therapy. 13 (14): 1501–11. doi:10.4161/cbt.22275. PMC   3542242 . PMID   22990204.
  2. ↑ Ma, Y; McCarty, SK; Kapuriya, NP; Brendel, VJ; Wang, C; Zhang, X; Jarjoura, D; Saji, M; Chen, CS; Ringel, MD (Aug 2013). "Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration". Journal of Clinical Endocrinology and Metabolism. 98 (8): E1314–22. doi:10.1210/jc.2012-3937. PMC   3733855 . PMID   23709653.
  3. ↑ Booth, L; Roberts, JL; Cruickshanks, N; Grant, S; Poklepovic, A; Dent, P (Oct 2014). "Regulation of OSU-03012 toxicity by ER stress proteins and ER stress-inducing drugs". Molecular Cancer Therapeutics. 13 (10): 2384–98. doi:10.1158/1535-7163.MCT-14-0172. PMC   4185238 . PMID   25103559. (This paper currently has an expression of concern, see doi:10.1158/1535-7163.MCT-19-0666)
  4. ↑ Liu, J; Qin, CK; Lv, W; Zhao, Q; Qin, CY (2013). "OSU-03012, a non-Cox inhibiting celecoxib derivative, induces apoptosis of human esophageal carcinoma cells through a p53/Bax/cytochrome c/caspase-9-dependent pathway" (PDF). Anticancer Drugs. 24 (7): 690–8. doi:10.1097/CAD.0b013e328362469f. PMID   23652278. S2CID   6028415. Archived from the original (PDF) on 2019-03-08.
  5. ↑ Koselny, K; Green, J; Favazzo, L; Glazier, VE; DiDone, L; Ransford, S; Krysan, DJ (8 Apr 2016). "Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase". ACS Infect Dis. 2 (4): 268–280. doi:10.1021/acsinfecdis.5b00134. PMC   4828684 . PMID   27088128.
  6. ↑ Koselny, K; Green, J; DiDone, L; Halterman, JP; Fothergill, AW; Wiederhold, NP; Patterson, TF; Cushion, MT; Rappelye, C; Wellington, M; Krysan, DJ (2016). "The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis". Antimicrob Agents Chemother. 60 (12): 7115–7127. doi:10.1128/AAC.01061-16. PMC   5118990 . PMID   27645246.
  7. ↑ Koselny, K; Green, J; DiDone, L; Halterman, JP; Fothergill, AW; Wiederhold, NP; Patterson, TF; Cushion, MT; Rappelye, C; Wellington, M; Krysan, DJ (2016). "The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis". Antimicrob Agents Chemother. 60 (12): 7115–7127. doi:10.1128/AAC.01061-16. PMC   5118990 . PMID   27645246.
  8. ↑ Collier, MA; Peine, KJ; Gautum, S; Oghumu, S; Varikuti, S; Borteh, H; Papenfuss, TL; Satoskar, AR; Bachelder, EM; Ainslie, KM (Feb 29, 2016). "Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles". International Journal of Pharmaceutics. 499 (1–2): 186–94. doi:10.1016/j.ijpharm.2016.01.004. PMC   5730989 . PMID   26768723.
  9. ↑ Ainslie; et al. "COMPOSITIONS AND METHODS FOR INHIBITING LEISHMANIA". Free Patents Online.
  10. ↑ Chiu, HC; Kulp, SK; Soni, S; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent". Antimicrob Agents Chemother. 53 (12): 5236–5244. doi:10.1128/aac.00555-09. PMC   2786354 . PMID   19805568.
  11. ↑ Hoang, KV; Borteh, HM; Rajaram, MV; Peine, KJ; Curry, H; Collier, MA; Homsy, ML; Bachelder, EM; Gunn, JS; Schlesinger, LS; Ainslie, KM (Dec 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". Int J Pharm. 477 (1–2): 334–343. doi:10.1016/j.ijpharm.2014.10.022. PMC   4267924 . PMID   25447826.
  12. ↑ Chiu, HC; Soni, S; Kulp, SK; Curry, H; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Francisella tularensis in THP-1 human macrophages with a novel autophagy inducing agent". J Biomed Sci. 16 (1): 110. doi: 10.1186/1423-0127-16-110 . PMC   2801672 . PMID   20003180.
  13. ↑ Hoang, KV; Curry, H; Collier, MA; Borteh, H; Bachelder, EM; Schlesinger, LS; Gunn, JS; Ainslie, KM (Mar 25, 2016). "Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge". Antimicrob Agents Chemother. 60 (4): 2052–62. doi:10.1128/AAC.02228-15. PMC   4808193 . PMID   26787696.
  14. ↑ Lo, JH; Kulp, SK; Chen, CS; Chiu, HC (Dec 2014). "Sensitization of intracellular Salmonella enterica serovar Typhimurium to aminoglycosides in vitro and in vivo by a host-targeted antimicrobial agent". Antimicrob Agents Chemother. 58 (12): 7375–82. doi:10.1128/AAC.03778-14. PMC   4249550 . PMID   25267669.
  15. ↑ Dent, Paul; et al. (2014). "GRP78 / BiP / HSPA5 / Dna K is a universal therapeutic target for human disease". Journal of Cellular Physiology. 230 (7): 1661–1676. doi:10.1002/jcp.24919. PMC   4402027 . PMID   25546329.
  16. ↑ Collier, MA; Gallovic, MD; Peine, KJ; Duong, AD; Bachelder, EM; Gunn, JS; Schlesingr, LS; Ainslie, KM (Nov 2013). "Delivery of host cell-directed therapeutics for intracellular pathogen clearance". Expert Rev Anti Infect Ther. 11 (11): 1225–1235. doi:10.1586/14787210.2013.845524. PMC   4070714 . PMID   24134600.
  17. ↑ Chiu, HC; Kulp, SK; Soni, S; Wang, D; Gunn, JS; Schlesinger, LS; Chen, CS (Dec 2009). "Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent". Antimicrob Agents Chemother. 53 (12): 5236–5244. doi:10.1128/aac.00555-09. PMC   2786354 . PMID   19805568.
  18. ↑ Hoang, KV; Borteh, HM; Rajaram, MV; Peine, KJ; Curry, H; Collier, MA; Homsy, ML; Bachelder, EM; Gunn, JS; Schlesinger, LS; Ainslie, KM (Dec 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". Int J Pharm. 477 (1–2): 334–343. doi:10.1016/j.ijpharm.2014.10.022. PMC   4267924 . PMID   25447826.
  19. ↑ Hoang, KV; Borteh, HM; Rajaram, MV; Peine, KJ; Curry, H; Collier, MA; Homsy, ML; Bachelder, EM; Gunn, JS; Schlesinger, LS; Ainslie, KM (Dec 2014). "Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection". Int J Pharm. 477 (1–2): 334–343. doi:10.1016/j.ijpharm.2014.10.022. PMC   4267924 . PMID   25447826.
  20. ↑ Hoang, KV; Curry, H; Collier, MA; Borteh, H; Bachelder, EM; Schlesinger, LS; Gunn, JS; Ainslie, KM (Mar 25, 2016). "Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge". Antimicrob Agents Chemother. 60 (4): 2052–62. doi:10.1128/AAC.02228-15. PMC   4808193 . PMID   26787696.
  21. ↑ Arno Therapeutics Inc receives European orphan drug designation for OSU-03012 to treat two infectious diseases. Reuters, 30 Apr 2015.
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.