Jonathan Z. Ho

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 μCi of [14C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (∼2 μM equivalents of [14C]anacetrapib) was achieved ∼4 h postdose. The parent compound was the major radioactive component (79–94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing ≤14% of the radioactivity in plasma or fecal samples. In vitro data indicated that anacetrapib is metabolized mainly by CYP3A4 to form M1, M2, and M3. Overall, these data, along with those from other preclinical and clinical studies, indicate that anacetrapib probably exhibits a low-to-moderate degree of oral absorption in humans and the absorbed fraction of the dose is eliminated largely via CYP3A4-catalyzed oxidative metabolism, followed by excretion of metabolites by the biliary-fecal route.

Pharmacokinetics, Metabolism, and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Rats and Rhesus Monkeys

The pharmacokinetics and metabolism of anacetrapib (MK-0859), a novel cholesteryl ester transfer protein inhibitor, were examined in rats and rhesus monkeys. Anacetrapib exhibited a low clearance in both species and a moderate oral bioavailability of ∼38% in rats and ∼13% in monkeys. The area under the plasma concentration-time curve in both species increased in a less than dose-proportional manner over an oral dose range of 1 to 500 mg/kg. After oral administration of [14C]anacetrapib at 10 mg/kg, ∼80 and 90% of the radioactive dose was recovered over 48 h postdose from rats and monkeys, respectively. The majority of the administered radioactive dose was excreted unchanged in feces in both species. Biliary excretion of radioactivity accounted for ∼15% and urinary excretion for less than 2% of the dose. Thirteen metabolites, resulting from oxidative and secondary glucuronic acid conjugation, were identified in rat and monkey bile. The main metabolic pathways consisted of O-demethylation (M1) and hydroxylation on the biphenyl moiety (M2) and hydroxylation on the isopropyl side chain (M3); these hydroxylations were followed by O-glucuronidation of these metabolites. A glutathione adduct (M9), an olefin metabolite (M10), and a propionic acid metabolite (M11) also were identified. In addition to parent anacetrapib, M1, M2, and M3 metabolites were detected in rat but not in monkey plasma. Overall, it appears that anacetrapib exhibits a low-to-moderate degree of absorption after oral dosing and majority of the absorbed dose is eliminated via oxidation to a series of hydroxylated metabolites that undergo conjugation with glucuronic acid before excretion into bile.

Uses of 1-Cyanoacetyl-4-phenyl-3-thiosemicarbazide in Heterocyclic Synthesis: Synthesis of Thiazole, Coumarin, and Pyridine Derivatives with Antimicrobial and Antifungal Activities

The reaction of cyanoacetyl hydrazine with phenylisothiocyanate gave the thiosemicarbazide 3 . The latter underwent a series of heterocyclization reactions when it reacts with either aromatic aldehydes or α -haloketones, follwed by further reaction of the products with cyanomethylene reagents or hydrazines to give either thiazole, coumarin, or pyridine derivatives. The newly synthesized product showed antimicrobial and antifungal activities.

Reaction of 3-Cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene with Enaminonitriles

Summary. 2-Amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with ethyl β-amino-α-cyano-γ-ethoxycarbonylcrotenoate yields the corresponding amide derivative. That compound reacts with benzenediazonium chloride to give the phenyl hydrazone derivative. This type of compounds was cyclized to give pyridazine and pyridine derivatives, respectively. Chemical reactivities of the latter were studied to give fused heterocyclic compounds with antimicrobial activities.