falciparum mouse model. The other four compounds were not progressed for the follow ing reasons CP 631992 is a neuropeptide Y5 receptor antagonist discontinued because of unfavourable animal toxicity findings. CE 245677 is NSC639966 a TIE2 tyrosine kinase inhibitor with reports of significant central nervous system adverse events at human plasma levels of 1. 5 uM. CJ 0231112 is a bradykinin B2 receptor antagonist and was rejected based on drug stability issues and the effect of food on absorption. and AG 024322, a CDK1/2/4/5 inhibitor, was known to have a narrow therapeutic window in mouse cancer models and demonstrated poor tolerability in Phase I studies. For the AZ set, 6/100 compounds had an EC50 1 uM. All six compounds originated from oncology programmes, mainly targeting human kinases.

Of these six compounds, AZ 4 targeting CDK2 and AZ 5 target ing aurora kinase were not progressed further because of toxicity concerns with these targets incompatible with an anti malarial therapy, specifically the essential role of CDK2 in maintaining genomic stability in mammals and myelosuppression associated with aurora kinase inhib ition. AZ 6 was not progressed because of poor selectivity with respect to HepG2 cytotoxicity. AZ 1 and AZ 2 are very closely related structurally. AZ 1 targets the Trk1 potassium transporter and AZ 2 targets JAK2, though both compounds have potential cardiovascular issues via hERG regulation. AZ 3 emerged from an on cology programme targeting human farnesyl transferase. AZ 1 and AZ 3 were further investigated for efficacy against P.

berghei with the aim that if the compounds showed efficacy, they could be considered as starting points for a lead optimization programme. Pharmacoki netic studies guided the selection of the 100 or 200 mg/kg BID dose used in the in vivo experiments. Oral amino benzotriazole 100 mg/kg was administered to inacti vate cytochrome P450 metabolism and increase drug bioavailability. However, both compounds were only marginally efficacious at high doses. The lack of convincing efficacy even at high doses coupled with concerns regard ing target selectivity and safety led to a halt in the further investigation of these compounds. Plasmodium falciparum huSCID mouse model The in vivo efficacy of four compounds was determined against P. falciparum in the humanized mouse model.

Two of these were identified in screening and two were sourced Drug_discovery additionally as a result of findings with related compounds during screening. The most active agent tested was UK 112,214, a water soluble PAF H1 inhibitor identified in the Pfizer STLAR screen. UK 112,214 had an ED90 of 131. 3 mg/kg, oral exposure was good, and the pharmacokinetic profile appeared linear within the dosing range. Exposure data from UK 112,214 treated mice versus parasitaemia fitted a sigmoid function. The estimated AUCED90 for UK 112,214 was 111. 5 ug h mL?1 day?1.