Ganaplacide Explained

Iupac Name:2-Amino-1-[2-(4-fluorophenyl)-3-[(4-fluorophenyl)amino]-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]ethanone
Legal Status:Investigational
Cas Number:1261113-96-5
Atc Prefix:None
Pubchem:49856296
Chemspiderid:28512871
Unii:85VMN9JU7A
Chembl:2058833
Synonyms:GNF-156, KAF156, Ganaplacide
C:22
H:23
F:2
N:5
O:1
Smiles:CC1(c2nc(c(n2CCN1C(=O)CN)Nc3ccc(cc3)F)c4ccc(cc4)F)C
Stdinchi: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
Stdinchikey: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

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. 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

The mechanism of this drug is currently unknown. Resistance is conferred by mutations in PfCARL, 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 that differs from the clinical candidate by a single halogen.

Society and culture

Economics

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

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]

Notes and References

  1. Held J, Jeyaraj S, Kreidenweiss A . Antimalarial compounds in Phase II clinical development . Expert Opinion on Investigational Drugs . 24 . 3 . 363–82 . March 2015 . 25563531 . 10.1517/13543784.2015.1000483 . 22547760 .
  2. Diagana TT . Supporting malaria elimination with 21st century antimalarial agent drug discovery . Drug Discovery Today . 20 . 10 . 1265–70 . October 2015 . 26103616 . 10.1016/j.drudis.2015.06.009 . free .
  3. White NJ, Duong TT, Uthaisin C, Nosten F, Phyo AP, Hanboonkunupakarn B, Pukrittayakamee S, Jittamala P, Chuthasmit K, Cheung MS, Feng Y, Li R, Magnusson B, Sultan M, Wieser D, Xun X, Zhao R, Diagana TT, Pertel P, Leong FJ . 6 . Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria . The New England Journal of Medicine . 375 . 12 . 1152–60 . September 2016 . 27653565 . 5142602 . 10.1056/NEJMoa1602250 .
  4. Meister S, Plouffe DM, Kuhen KL, Bonamy GM, Wu T, Barnes SW, Bopp SE, Borboa R, Bright AT, Che J, Cohen S, Dharia NV, Gagaring K, Gettayacamin M, Gordon P, Groessl T, Kato N, Lee MC, McNamara CW, Fidock DA, Nagle A, Nam TG, Richmond W, Roland J, Rottmann M, Zhou B, Froissard P, Glynne RJ, Mazier D, Sattabongkot J, Schultz PG, Tuntland T, Walker JR, Zhou Y, Chatterjee A, Diagana TT, Winzeler EA . 6 . Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery . Science . 334 . 6061 . 1372–7 . December 2011 . 22096101 . 3473092 . 10.1126/science.1211936 . 2011Sci...334.1372M .
  5. Nagle A, Wu T, Kuhen K, Gagaring K, Borboa R, Francek C, Chen Z, Plouffe D, Lin X, Caldwell C, Ek J, Skolnik S, Liu F, Wang J, Chang J, Li C, Liu B, Hollenbeck T, Tuntland T, Isbell J, Chuan T, Alper PB, Fischli C, Brun R, Lakshminarayana SB, Rottmann M, Diagana TT, Winzeler EA, Glynne R, Tully DC, Chatterjee AK . 6 . Imidazolopiperazines: lead optimization of the second-generation antimalarial agents . Journal of Medicinal Chemistry . 55 . 9 . 4244–73 . May 2012 . 22524250 . 3350218 . 10.1021/jm300041e .
  6. Kuhen KL, Chatterjee AK, Rottmann M, Gagaring K, Borboa R, Buenviaje J, Chen Z, Francek C, Wu T, Nagle A, Barnes SW, Plouffe D, Lee MC, Fidock DA, Graumans W, van de Vegte-Bolmer M, van Gemert GJ, Wirjanata G, Sebayang B, Marfurt J, Russell B, Suwanarusk R, Price RN, Nosten F, Tungtaeng A, Gettayacamin M, Sattabongkot J, Taylor J, Walker JR, Tully D, Patra KP, Flannery EL, Vinetz JM, Renia L, Sauerwein RW, Winzeler EA, Glynne RJ, Diagana TT . 6 . 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 . September 2014 . 24913172 . 4135840 . 10.1128/AAC.02727-13 .
  7. Leong FJ, Zhao R, Zeng S, Magnusson B, Diagana TT, Pertel P . 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 . November 2014 . 25136017 . 4249437 . 10.1128/AAC.03478-14 .
  8. White NJ, Duong TT, Uthaisin C, Nosten F, Phyo AP, Hanboonkunupakarn B, Pukrittayakamee S, Jittamala P, Chuthasmit K, Cheung MS, Feng Y, Li R, Magnusson B, Sultan M, Wieser D, Xun X, Zhao R, Diagana TT, Pertel P, Leong FJ . 6 . Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria . EN . The New England Journal of Medicine . 375 . 12 . 1152–60 . September 2016 . 27653565 . 5142602 . 10.1056/nejmoa1602250 .
  9. Lim MY, LaMonte G, Lee MC, Reimer C, Tan BH, Corey V, Tjahjadi BF, Chua A, Nachon M, Wintjens R, Gedeck P, Malleret B, Renia L, Bonamy GM, Ho PC, Yeung BK, Chow ED, Lim L, Fidock DA, Diagana TT, Winzeler EA, Bifani P . 6 . UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes . Nature Microbiology . 1 . 12 . 16166 . September 2016 . 27642791 . 5575994 . 10.1038/nmicrobiol.2016.166 .
  10. LaMonte G, Lim MY, Wree M, Reimer C, Nachon M, Corey V, Gedeck P, Plouffe D, Du A, Figueroa N, Yeung B, Bifani P, Winzeler EA . 6 . Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance . mBio . 7 . 4 . e00696–16 . July 2016 . 27381290 . 4958248 . 10.1128/mBio.00696-16 .
  11. News: Experimental treatment clears malaria infections in small clinical study Novartis. Novartis. 2016-11-18. 2016-11-18. https://web.archive.org/web/20161118100637/https://www.novartis.com/stories/global-impact/experimental-treatment-clears-malaria-infections-small-clinical-study. dead.
  12. Web site: Novartis expands partnership with Medicines for Malaria Venture to develop next-generation antimalarial treatment. malaria.novartis.com. 2016-11-18.
  13. US . 20130281403 . Compounds and compositions for the treatment of parasitic diseases . Chatterjee AK, Nagle AS, Wu T, Tully DC, Kuhen KL . Novartis AG . 18 October 2016 .
  14. Web site: UNII-85VMN9JU7A C22H23F2N5O - . PubChem . U.S. National Library of Medicine . 2016-11-18.

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