Absorption, distribution, metabolism, and excretion of CKD-732, a novel antiangiogenic fumagillin derivative, in rats, mice, and dogs.

The pharmacokinetics of CKD-732 (6-O-4-[dimethyl-aminoethoxy)cinnamoyl]-fumagillol x hemioxalate) was investigated in male SD rats and beagle dogs after bolus intravenous administration. The parent compound and metabolites obtained from in vitro and in vivo samples were determined by LC/MS. The main metabolite was isolated and identified as an N-oxide form of CKD-732 by NMR and LC/MS/MS. CKD-732 was metabolized into either M11 or others by rapid hydroxylation, demethylation, and hydrolysis. The blood level following the intravenous route declined in first-order kinetics with T(1/2)beta values of 0.72 to approximately 0.78 h for CKD-732 and 0.92 to approximately 1.09 h for M11 in rats at a dose of 7.5 to approximately 30 mg/kg. In dogs, T(1/2)beta values of CKD-732 and M11 were 1.54 and 1.79 h, respectively. Moreover, AUC values increased dose dependently for CKD-732 and M11 in rats and dogs. The CLtot and Vdss did not change significantly with increasing dose, indicating linear pharmacokinetic patterns. The excretion patterns through the urine, bile, and feces were also examined in the animals. The total amount excreted in urine, bile, and feces was 2.13% for CKD-732 and 1.29% for M11 in rats, and 1.58% for CKD-732 and 2.28% for M11 in dogs.

Safety pharmacology of CKD-602, a novel anticancer agent.

CKD-602 ((20S)-7-[2-(N-isopropylamino)-ethyl]-camptothecin.HCl, CAS 213819-48-8) is a new class of anticancer drug that belongs to the topoisomerase inhibitors. Its effect on the central nervous system (CNS), general behavior, cardiovascular-respiratory system and the other organ systems were studied. When intravenously administered, CKD-602 up to doses of 5 mg/kg caused an increase of body temperature, increase of respiration rate, decrease of gastrointestinal transport, showed analgesic action and produced antisecretory action in pylorus ligated rats. However, CKD-602 showed no effects on general behavior, motor coordination, spontaneous locomotor activity, hexobarbital sleeping time, convulsion, cardiovascular, smooth muscle and urinary tract system. These findings demonstrate that CKD-602 in doses up to 5 mg/kg has minor effects on the CNS in animals. However, CKD-602 does not exert any general pharmacological effects at the dose of 1 mg/kg except the effects on gastric secretion.

Synthesis of 6-formyl-pyridine-2-carboxylate derivatives and their telomerase inhibitory activities.

Twenty-one pyridine-2-carboxylate derivatives were prepared by the coupling of 6-formyl-2-carboxylic acid with the corresponding phenol, thiophenol, and aniline, substituted with various functional groups. Among them, the 3,4-dichlorothiophenol ester (9p) showed the highest in vitro telomerase inhibitory activity and quite significant in vivo tumor suppression activity.

The identification of in vitro metabolites of CKD-732 by liquid chromatography/tandem mass spectrometry.

The structural elucidation of fourteen metabolites of CKD-732, formed in vitro with rat liver microsomes, was performed using high-performance liquid chromatography/electrospray ionization-tandem mass spectrometry (HPLC/ESI-MS/MS). To identify proposed structures of the metabolites, the product ion mass spectra of the protonated molecules ([M + H]+), the retention times on reversed-phase HPLC, and UV-Vis spectra were utilized. Characteristic product ions for the identification of CKD-732 metabolites were observed at m/z 231, 236, and 252. The fragment ions at m/z 236 and 252 indicated the unchanged form and the N-oxide of the dimethylaminoethoxycinnamoyl group, respectively. The ion at m/z 231 indicated the presence of the hydroxylated form of the fumagillol group. The N-oxide of CKD-732, which was detected at m/z 515 and eluted later than CKD-732 in the reversed-phase HPLC system, was measured as a major metabolite. Three cis-trans isomers were also found.

Novel alpha-glucosidase inhibitors, CKD-711 and CKD-711a produced by Streptomyces sp. CK-4416. II. Biological properties.

CKD-711 and CKD-711a are aminooligosaccharide alpha-glucosidase inhibitors discovered during the bioactive material screening for antibacterial agent. Their inhibitory activities were studied and compared with those of acarbose in vitro and in vivo with animals. In in vitro study, CKD-711 showed similar effects to acarbose on porcine intestinal maltase and sucrase, IC50s of 2.5 and 0.5 microg/ml, respectively, whereas it had about 2 fold lower alpha-amylase inhibitory activity (IC50, 78.0 microg/ml) than acarbose (IC50, 36 microg/ml). CKD-711a showed less inhibitory activity than CKD-711 against all the enzymes tested. In rat fed on starch and sucrose meals, the dose of CKD-711 which reduced the postprandial blood glucose increment by 50 percent in comparison to control rats (ED50) were 3.07 and 1.15 mg/kg, respectively, and acarbose had ED50s of 1.94 and 1.15 mg/kg, respectively. CKD-711 and CKD-711a also showed antibacterial activity against Comamonas terrigena.