Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC 50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei -infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.

We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.

Malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. Even inhabitants of temperate zones are exposed to the danger of malaria infection because of travel and global warming. Novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. A search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. The derivative SSJ-183 (5), having a 4-aminopyridine group, showed an IC 50 value against Plasmodium falciparum of 7.6 nM and a selectivity index of >7300. Cure was achieved by three oral doses of 5 at 100 mg/kg to mice infected with the Plasmodium berghei ANKA strain. The safety of 5 was supported by acute toxicity testing in mice with single doses up to 2000 mg/kg po, chromosome aberration test, in vitro as well as in vivo micronucleus tests, and phototoxicity studies in mice. Thus, 5 is a promising candidate as a new antimalarial agent.

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The present study investigated the effects of a functional deficit in insulin-like growth factor-I signaling via chronic intravenous administration of insulin-like growth factor-I (IGF-I) receptor antisense in the conscious spontaneously hypertensive rat cardiovascular system. Insulin-like growth factor-I receptor (IGF-IR) antisense, but not full mismatch treatment, decreased IGF-IR expression in both conductance and resistance blood vessels. Aortic IGF-IR density was reduced by 67.4 Ϯ 6.0% in antisense-treated spontaneously hypertensive rat (SHR) compared with untreated animals, whereas mismatch treatment had no effect (analysis of variance, n ϭ 3, P Ͻ 0.01). Aortic and tail artery angiotensin II type 1 receptor expression was significantly reduced by IGF-IR antisense treatment, whereas angiotensin II type 2 receptor expression was unaffected by administration of antisense and mismatch oligonucleotides. IGF-I receptor antisense treatment caused a significant decrease in pressor responses to angiotensin II in comparison with fulllength mismatch treatment (E max was reduced to 65 Ϯ 7 mm Hg compared with 99 Ϯ 6 mm Hg, p Ͻ 0.05). Likewise, a reduction in pressor responses to noradrenaline was observed in hypertensive rats treated with IGF-IR antisense compared with full mismatch-treated rats (E max was reduced to 60 Ϯ 6 mm Hg compared with 108 Ϯ 5 mm Hg, p Ͻ 0.01). There was no clear antisense effect on resting blood pressure and no effect at on aortic medial thickness. These results suggest that although the proliferative and vasodilator effects of IGF-I are impaired in SHR, the effects on angiotensin receptor expression remain profound.A number of differences in the cardiovascular effects of insulin-like growth factor-I (IGF-I) have been identified in hypertensive animal models compared with their normotensive counterparts. Among the many growth-promoting effects of IGF-I is a role as a potent vascular smooth muscle cell mitogen (Du and Delafontaine, 1995), and this proliferative response is blunted in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) (Nolan et al., 2003). An increase in IGF-I mRNA expression, however, is seen in rat models of hypertrophying aorta, portal vein, or urinary bladder (Khorsandi et al., 1992;Chen et al., 1994). IGF-I also causes direct vasodilation via a nitric oxide-dependent pathway Walsh et al., 1996) and relaxes aortic rings precontracted with phenylephrine, an effect also impaired in SHR (Vecchione et al., 2001). Thus, in the vasculature, IGF-I has both pressor-inducing (VSMC mitogenic effect) and depressor effects, and both are altered in hypertensive models, whereas the expression of both the ligand and its receptor may increase in such circumstances.There are profound interactions between IGF-I and the renin-angiotensin system with respect to vascular resistance. In VSMC, angiotensin II has been shown to potentiate IGF-I and IGF-IR expression, and this potentiation has been found to be important in the vascular growth-promoting effects of a...