Compounds having antiparasitic or anti-infectious activity
OHSU # 1238
ENDOCHIN-LIKE QUINOLONE PROGRAM
OHSU Technology 1238
The development of the ELQ program was in partnership with investigators at Medicines for Malaria Venture (MMV) and University of South Florida. Superior features of an optimized lead include: low nanomolar IC50s vs. P. falciparum and P. vivax parasites including the atovaquone resistant C2B strain, high metabolic stability (EH < 0.2 human microsomes), high activity by oral route (GSK Py 4 day test: ED50 = 0.1mg/kg/d, ED90 = 0.15mg/kg/d, ED99 = 0.24mg/kg/d, NRD = 1mg/kg/day), and high selectivity for the parasite enzyme target (P. falciparum cyt bc1 IC50 = 0.58nM; P. yoelii cyt bc1 IC50 = 21nM; human cyt bc1 IC50> 10,000nM; P. falciparum and P. vivax field isolates ex vivo EC50 = 14.9 nM and 17.9 nM respectively).
The optimized lead is a small molecule active on a clinically validated pathway that overcomes the shortcomings of its progenitor (atovaquone). The compound is potent in vitro against all blood stage falciparum strains including those resistant to both atovaquone and a 4-(1H)-pyridone. Interestingly, the molecule is also exquisitely potent against exo-erythrocytic stages and impacts not only liver schizonts, but also inhibits exflagellation and ookinete formation in the mosquito midgut. In vivo doses lower than the ED90 result in formal causal prophylaxis and killing of all P. berghei liver schizonts (0.03mg/kg); furthermore such a dose also results in complete inhibition of P. berghei oocyst formation in a mouse feeding study thus totally inhibiting sporogony and demonstrating a 100% block of transmission. This compound has high in vitro selectivity over human cytochrome bc1 and various mammalian cell lines. It was not inhibitory against a large safety and selectivity target panel of receptors, amine transporters and ion channels, including the hERG channel, nor is the compound genotoxic (as assessed in a GLP 5-strain Ames and non-GLP in vitro micronucleus assays). In line with a low predicted dose in patients, and a long predicted human half-life, the compound may offer the potential as a combination partner aimed at a single dose cure. The effects on exoerythrocytic stages, furthermore, offer not only the hope of a new molecule to help cure patients, but also to block transmission and prophylaxis, thus breaking the parasite lifecycle.
ELQ’s and additional Parasitic Infections
Endochin-like quinolones are highly efficacious against acute and latent experimental Toxoplasma gondii, and Trypanosma cruzi in relevant animal models, see relevant publication below. Further data may be provided upon request.
Technology 1238 – Patent Published, PCT WO2010/065905; Patents have issued in certain territories.
Technology 1238 is available for exclusive licensing.
Relevant Publication s
Riscoe, MK et al., 2013. Quinolone-3-Diarylethers: A New Class of Antimalarial Drug, Sci. Transl. Med. 5(177):Early Edition.
Riscoe, MK et al., 2012. Endochin-Like Quinolones are Highly Efficacious Against Acute and latent experimental toxoplasmosis, Proc Natl Acad Sci U S A. 109(39):15936-41.
- Michael Riscoe, SM.MMBI Administration
- Rolf Winter
- Jane Kelly
- David Hinrichs
- Martin Smilkstein
- Aaron Nilsen, SM.MMBI Admin
For more information, contact:
Senior Technology Development Manager