Decreased serum and hepatic cholesterol concentrations in the cholesterol-fed rat. Subsequent papers will describe the structure-activity studies that led to the selection of 1, the pharmacokinetic investigation used to characterize the absorption and metabolism of the compound, and the hypocholesterolemic activity of 1 in other species. Compound 1 is about to enter clinical trials as a hypolipidemic/antiatherosclerotic agent. Despite the availability and optimal use of several antiepileptic drugs, many patients with epilepsy do not experience satisfactory seizure control with them, or they do so at the expense of significant side effects. Phenytoin, first marketed in 1938, is still the drug of choice for the treatment of many epileptic seizures despite its side effects and other disadvantages. New antiepileptic drugs with fewer side effects and lower toxicity are needed. As part of a program for new antiepileptic drugs with improved properties, a number of compounds were tested for anticonvulsant activity in several animal models. From this program emerged 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (BW A78U (1)), a novel, orally active anticonvulsant with potent activity against maximal electroshock-induced seizures (MES) in animal models that predict antiepileptic activity in man. The synthesis and structure-activity relationships of a number of 1,3-bis(aryloxy)propanes, which are in vivo antagonists of LTD4 in the guinea pig, are described. One of these compounds, 4 (Wy-44,329), was not only approximately equipotent with the standard 1 (FPL 55712) in the LTC4 (ID50 = 0.17 and 0.23 mg/kg iv, respectively) and LTD4 (ID50 = 0.11 and 0.15 mg/kg iv, respectively) challenge models but also possessed greater potency in the ovalbumin challenge model (ID50 = 0.47 mg/kg and 4.1 mg/kg iv, respectively) and a longer duration of action. This compound was a competitive LTD4 antagonist on guinea pig ileum (pA2 = 9.4) and possessed mediator release (rat PCA, ID50 = 0.26 mg/kg iv) and 5-lipoxygenase (IC50 = 32 μM vs. 5-HETE) inhibitory activities.