Ganaplacide

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Ganaplacide
Clinical data
Other namesGNF-156, KAF156, Ganaplacide
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
  • 2-Amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]ethanone
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC22H23F2N5O
Molar mass411.457 g·mol−1
3D model (JSmol)
  • CC1(c2nc(c(n2CCN1C(=O)CN)Nc3ccc(cc3)F)c4ccc(cc4)F)C
  • InChI=1S/C22H23F2N5O/c1-22(2)21-27-19(14-3-5-15(23)6-4-14)20(26-17-9-7-16(24)8-10-17)28(21)11-12-29(22)18(30)13-25/h3-10,26H,11-13,25H2,1-2H3
  • Key:BUPRVECGWBHCQV-UHFFFAOYSA-N

Ganaplacide (development code KAF156) is a drug in development by Novartis for the purpose of treating malaria. It belongs to the class of the imidazolopiperazines.[1][2] It has shown activity against the Plasmodium falciparum and Plasmodium vivax forms of the malaria parasite.[3]

Clinical development[edit]

The antimalarial activity of the imidazolopiperazine compound class was initially discovered through a series of sensitive phenotypic antimalarial screens that were developed and run in 2007 and 2008 by a group of biologists[4] working at the Genomics Institute of the Novartis Research Foundation and the Scripps Research Institute. The lead product was published in 2012 as a leader of the imidazolopiperazine class.[5] This was followed by studies in animal models published in 2014.[6] Preclinical studies found no significant in vitro safety liabilities.[6] A Phase 1 study found some gastrointestinal and neurological effects but these were self-limited in 70 healthy males and established dosing for a future Phase 2 Trial.[7]

The just completed Phase 2 Trial was completed with 4 study locations in Thailand and one study location in Vietnam. This study looked at the effect of 400 mg given daily for 3 days as well as a single 800 mg dose. In the 21 Patients who received a single 800 mg dose 67% of patients cleared the infection which is comparable to other antimalarial medications. More than half of the patients had some reported adverse event and the rate was higher in patients who received a single 800 mg dose over patients who received 3 400 mg doses. The most common effect was asymptomatic bradycardia where patients heart rates fell below 60 Beats Per Minute. Other reported events include hypokalemia, elevated liver enzymes as well as anemia.[8]

Pharmacology[edit]

The mechanism of this drug is currently unknown. Resistance is conferred by mutations in PfCARL,[4][6] a protein with 7 transmembrane domains, as well as by mutations in the P. falciparum acetyl-CoA transporter and the UDP-galactose transporter.[9] None of these are thought to be the target of ganaplacide.[10] Initial functional studies were performed with the closely related chemotype, GNF179[4] that differs from the clinical candidate by a single halogen.[clarification needed]

Society and culture[edit]

Economics[edit]

Novartis is an international drug company based in Switzerland and is developing ganaplacide as a drug for the treatment of malaria. This drug was identified by a high throughput screen of over 2 million compounds.[11] This drug is being developed with support from the Bill and Melinda Gates foundation via their Medicine for Malaria Venture. It will also be a part of the Novartis Malaria Initiative which has been providing 750 million treatments without producing any profit for the larger company.[12]

Intellectual property[edit]

Ganaplacide is protected by the granted United States Patent 20130281403 held by the inventors, Arnab Chatterjee, Advait Nagle, Tao Wu, David Tully, and Kelli Kuhen, and filed June 7, 2013.[13] There are previous US patent applications but only this one has been granted.[14]

References[edit]

  1. ^ Held J, Jeyaraj S, Kreidenweiss A (March 2015). "Antimalarial compounds in Phase II clinical development". Expert Opinion on Investigational Drugs. 24 (3): 363–82. doi:10.1517/13543784.2015.1000483. PMID 25563531. S2CID 22547760.
  2. ^ Diagana TT (October 2015). "Supporting malaria elimination with 21st century antimalarial agent drug discovery". Drug Discovery Today. 20 (10): 1265–70. doi:10.1016/j.drudis.2015.06.009. PMID 26103616.
  3. ^ White NJ, Duong TT, Uthaisin C, Nosten F, Phyo AP, Hanboonkunupakarn B, et al. (September 2016). "Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria". The New England Journal of Medicine. 375 (12): 1152–60. doi:10.1056/NEJMoa1602250. PMC 5142602. PMID 27653565.
  4. ^ a b c Meister S, Plouffe DM, Kuhen KL, Bonamy GM, Wu T, Barnes SW, et al. (December 2011). "Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery". Science. 334 (6061): 1372–7. Bibcode:2011Sci...334.1372M. doi:10.1126/science.1211936. PMC 3473092. PMID 22096101.
  5. ^ Nagle A, Wu T, Kuhen K, Gagaring K, Borboa R, Francek C, et al. (May 2012). "Imidazolopiperazines: lead optimization of the second-generation antimalarial agents". Journal of Medicinal Chemistry. 55 (9): 4244–73. doi:10.1021/jm300041e. PMC 3350218. PMID 22524250.
  6. ^ a b c Kuhen KL, Chatterjee AK, Rottmann M, Gagaring K, Borboa R, Buenviaje J, et al. (September 2014). "KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission". Antimicrobial Agents and Chemotherapy. 58 (9): 5060–7. doi:10.1128/AAC.02727-13. PMC 4135840. PMID 24913172.
  7. ^ Leong FJ, Zhao R, Zeng S, Magnusson B, Diagana TT, Pertel P (November 2014). "A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers". Antimicrobial Agents and Chemotherapy. 58 (11): 6437–43. doi:10.1128/AAC.03478-14. PMC 4249437. PMID 25136017.
  8. ^ White NJ, Duong TT, Uthaisin C, Nosten F, Phyo AP, Hanboonkunupakarn B, et al. (September 2016). "Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria". The New England Journal of Medicine. 375 (12): 1152–60. doi:10.1056/nejmoa1602250. PMC 5142602. PMID 27653565.
  9. ^ Lim MY, LaMonte G, Lee MC, Reimer C, Tan BH, Corey V, et al. (September 2016). "UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes". Nature Microbiology. 1 (12): 16166. doi:10.1038/nmicrobiol.2016.166. PMC 5575994. PMID 27642791.
  10. ^ LaMonte G, Lim MY, Wree M, Reimer C, Nachon M, Corey V, et al. (July 2016). "Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance". mBio. 7 (4): e00696–16. doi:10.1128/mBio.00696-16. PMC 4958248. PMID 27381290.
  11. ^ "Experimental treatment clears malaria infections in small clinical study | Novartis". Novartis. Retrieved 2016-11-18.
  12. ^ "Novartis expands partnership with Medicines for Malaria Venture to develop next-generation antimalarial treatment". malaria.novartis.com. Retrieved 2016-11-18.
  13. ^ US 20130281403, Chatterjee AK, Nagle AS, Wu T, Tully DC, Kuhen KL, "Compounds and compositions for the treatment of parasitic diseases", issued 18 October 2016, assigned to Novartis AG 
  14. ^ "UNII-85VMN9JU7A | C22H23F2N5O -". PubChem. U.S. National Library of Medicine. Retrieved 2016-11-18.
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