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1.
J Med Chem ; 56(6): 2547-55, 2013 Mar 28.
Article in English | MEDLINE | ID: mdl-23489135

ABSTRACT

To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.


Subject(s)
Antimalarials/metabolism , Antimalarials/pharmacology , Dioxolanes/chemistry , Tetraoxanes/chemistry , Absorption , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/metabolism , Adamantane/pharmacokinetics , Adamantane/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/metabolism , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds, 1-Ring/chemistry , Heterocyclic Compounds, 1-Ring/metabolism , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Heterocyclic Compounds, 1-Ring/pharmacology , Male , Mice , Peroxides/chemistry , Peroxides/metabolism , Peroxides/pharmacokinetics , Peroxides/pharmacology , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity Relationship
2.
J Med Chem ; 53(1): 481-91, 2010 Jan 14.
Article in English | MEDLINE | ID: mdl-19924861

ABSTRACT

The structure and stereochemistry of the cyclohexane substituents of analogues of arterolane (OZ277) had little effect on potency against Plasmodium falciparum in vitro. Weak base functional groups were not required for high antimalarial potency, but they were essential for high antimalarial efficacy in P. berghei-infected mice. Five new ozonides with antimalarial efficacy and ADME profiles superior or equal to that of arterolane were identified.


Subject(s)
Antimalarials/pharmacology , Heterocyclic Compounds, 1-Ring/pharmacology , Peroxides/pharmacology , Plasmodium falciparum/drug effects , Spiro Compounds/pharmacology , Animals , Antimalarials/adverse effects , Antimalarials/chemistry , Antimalarials/therapeutic use , Heterocyclic Compounds, 1-Ring/chemical synthesis , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Heterocyclic Compounds, 1-Ring/therapeutic use , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Mice , Molecular Conformation , Parasitic Sensitivity Tests , Peroxides/chemical synthesis , Peroxides/pharmacokinetics , Peroxides/therapeutic use , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Spiro Compounds/therapeutic use , Stereoisomerism , Structure-Activity Relationship
3.
J Med Chem ; 51(4): 1035-42, 2008 Feb 28.
Article in English | MEDLINE | ID: mdl-18232653

ABSTRACT

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.2 days with this oral dose regimen. In comparison, animals receiving no drug die typically on day 6-7 postinfection. At only 3 x 10 mg/kg oral dosing, seven dimers prolong the lifetime of malaria-infected mice to days 14-17, more than double the chemotherapeutic effect of sodium artesunate. Ten new trioxane dimers at only a single oral dose of 30 mg/kg prolong mouse average survival to days 8.7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials.


Subject(s)
Antimalarials/chemical synthesis , Artemisinins/chemical synthesis , Malaria/drug therapy , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Artemisinins/chemistry , Artemisinins/therapeutic use , Mice , Plasmodium berghei , Structure-Activity Relationship
4.
Exp Parasitol ; 115(3): 296-300, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17087929

ABSTRACT

RBx11160 (OZ277) is a promising antimalarial drug candidate that Ranbaxy Laboratories Limited and Medicines for Malaria Venture (MMV) are currently developing as a fixed combination with piperaquine. Here, we describe the in vitro (Plasmodium falciparum) and in vivo (Plasmodium berghei) activities of piperaquine in combination with RBx11160 and artemether. In vitro, both combinations demonstrated a slight tendency towards antagonism with mean sums of fractional inhibitory concentrations (mean Sigma FICs) of 1.5. In vivo, piperaquine and artemether were borderline antagonistic (mean Sigma FIC of 1.4). However, an additive in vivo interaction of piperaquine and RBx11160 (mean Sigma FIC of 1.1) was identified, suggesting that a RBx11160-piperaquine combination therapy in humans should allow each molecule to exert its full antimalarial effect.


Subject(s)
Antimalarials/pharmacology , Heterocyclic Compounds, 1-Ring/pharmacology , Malaria/drug therapy , Peroxides/pharmacology , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Quinolines/pharmacology , Spiro Compounds/pharmacology , Animals , Antimalarials/therapeutic use , Artemether , Artemisinins/pharmacology , Artemisinins/therapeutic use , Atovaquone/pharmacology , Disease Models, Animal , Drug Interactions , Drug Therapy, Combination , Erythrocytes/parasitology , Female , Heterocyclic Compounds, 1-Ring/therapeutic use , Humans , Malaria/parasitology , Mice , Parasitemia/drug therapy , Parasitemia/parasitology , Parasitic Sensitivity Tests , Peroxides/therapeutic use , Pyrimethamine/pharmacology , Pyrimethamine/therapeutic use , Quinolines/therapeutic use , Spiro Compounds/therapeutic use
5.
J Med Chem ; 48(15): 4953-61, 2005 Jul 28.
Article in English | MEDLINE | ID: mdl-16033274

ABSTRACT

This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.


Subject(s)
Antimalarials/chemical synthesis , Malaria/drug therapy , Ozone/chemistry , Peroxides/chemical synthesis , Spiro Compounds/chemical synthesis , Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Adamantane/pharmacology , Adamantane/toxicity , Animals , Antimalarials/pharmacology , Antimalarials/toxicity , Cell Line, Tumor , Drug Resistance , Half-Life , Malaria, Falciparum/drug therapy , Mice , Micronucleus Tests , Peroxides/pharmacology , Peroxides/toxicity , Plasmodium berghei , Rats , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship
6.
Nature ; 430(7002): 900-4, 2004 Aug 19.
Article in English | MEDLINE | ID: mdl-15318224

ABSTRACT

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)--may be critical to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indices and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chemical (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (non-compliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Artemisinins/chemistry , Drug Design , Drug Evaluation, Preclinical , Heterocyclic Compounds, 1-Ring/chemical synthesis , Heterocyclic Compounds, 1-Ring/pharmacology , Peroxides , Sesquiterpenes/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacokinetics , Biological Availability , Half-Life , Heterocyclic Compounds, 1-Ring/chemistry , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Humans , Inhibitory Concentration 50 , Malaria/drug therapy , Malaria/metabolism , Malaria/parasitology , Mice , Oxidation-Reduction , Plasmodium berghei/drug effects , Plasmodium berghei/physiology , Plasmodium falciparum/drug effects , Rats , Rats, Wistar , Solubility , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Tissue Distribution
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