Piperidine renin inhibitors: from leads to drug candidates.

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.

Animal pharmacokinetics and metabolism of the new antimalarial Ro 42-1611 (arteflene).

Ro 42-1611 (arteflene) is a new synthetic structural analogue of yingzhaosu, a Chinese traditional herbal drug, now under development for treatment of malaria. The in vivo activity of arteflene in a mouse animal model was 4-5 fold higher after parenteral than after oral administration. Pharmacokinetics of the drug were investigated in mice, rats, dogs, marmosets and cynomolgus monkeys. Plasma concentrations of arteflene were determined using a specific HPLC-UV method; the limit of quantification was 45 ng/ml using 0.5 ml plasma. The oral bioavailability was very low and variable (0.6% in mice, 4-5% in rats, 2.5 +/- 1% in dogs, < or = 0.5% in marmosets and < 0.5% in cynomolgus) as expected from the high metabolic clearance and the relative short apparent half-life (1.4-4.7 h). However, a metabolite (MA) was observed in plasma of all species indicating that drug was absorbed but underwent extensive first-pass metabolism. MA was also detected in samples of human plasma, collected during an oral tolerability study in healthy volunteers. After incubation of 14C-arteflene with liver microsomes of mice, rats, dogs and humans, the same major metabolite was detected and both samples were identical to Ro 47-6936 which was chemically synthesized as a reference compound. The in vitro activity of Ro 47-6936 was tested against Plasmodium falciparum and found to be about 1/4 that of the parent drug. Therefore, this metabolite makes a significant contribution to the biological activity in vivo, partially explaining the high activity of arteflene after oral administration in spite of its low bioavailability. Moreover, comparison of the metabolic patterns from human, rat and dog microsomes indicated that the dog is an appropriate species for toxicological evaluations.