Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors.

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

Pharmacokinetics of TDP223206 following intravenous and oral administration to intact rats and intravenous administration to bile duct-cannulated rats.

The pharmacokinetics of TDP223206 was studied following single intravenous and oral administrations in rats. A mixture of TDP223206 and (14)C-TDP223206 were administered to intact and bile duct-cannulated rats. Following intravenous administration, plasma concentrations declined biphasically. The AUC(inf) increased linearly with dose but was not dose proportional. The PK parameters of TDP223206 indicated low clearance (254-386 ml/h/kg) and a moderate volume of distribution (968-1883 ml/kg). The bioavailability was 32.95% and 24.46% for 10 and 50 mg/kg oral doses, respectively. (14)C-TDP223206 was distributed widely into different tissues with small intestine, liver, kidneys and large intestine having large tissue to plasma ratios. (14)C-TDP223206 was the major circulating component in the plasma. A total of 91.2% of administered radioactivity of (14)C-TDP223206 was recovered in bile indicating that biliary excretion was the major pathway for drug elimination. (14)C-TDP223206-acyl glucuronides were the major metabolites in bile. The oxo-(14)C-TDP223206 was the major metabolite in plasma and an important metabolite in bile. Two forms of diastereomeric acyl glucuronides of (14)C-TDP223206 were detected in bile with similar LC/MS intensities suggesting a similar biotransformation capacity. Only one form of these (14)C-TDP223206-acyl glucuronides was detected in plasma suggesting that enterohepatic recirculation was related to the nature of the stereo-isomers.

Pharmacokinetic properties of TDP4815 after single intravenous and oral administrations to rat, rabbit, monkey, dog and in vitro drug metabolism.

The pharmacokinetics of TDP4815 was evaluated in rats, rabbits, dogs and monkeys. After intravenous administration, TDP4815 achieved C(O) of 3255 ng/ml in rats at 5 mg/kg, 9066 ng/ml in rabbits and 7858 ng/ml in monkeys at 6 mg/kg, and 4457 ng/ml in dogs at 3 mg/kg. The clearance (C(L)) was 3105, 1692, 835 and 640 ml/h/kg in rats, rabbits, monkeys and dogs, respectively. The volume of distribution (V(Z)) was more than 3861 ml/kg in all species, except 1915 ml/kg in monkeys. The oral bioavailability was rabbit >rat> monkey compared at 100 mg/kg, but it was much higher in dogs (>64%) after oral administrations. The calculated intrinsic clearance data suggested that the clearance of dog and human was restricted by binding to the plasma protein, and the clearance of rat and monkey was dependent on both the free fraction of plasma protein binding and the liver blood flow rate. The unbound hepatic intrinsic clearance of monkey was close to its C(L) suggesting that the hepatic clearance was an important excretion in monkeys. The poor oral bioavailability in the monkey may be related to the extensive glucuronidation. The V(Z).kg and C(L).kg in test species showed good correlation with the animal body weights (R(2)=0.87 and 0.96).

Human oral drugs absorption is correlated to their in vitro uptake by brush border membrane vesicles.

Brush border membrane vesicles (BBMV) were prepared from the rabbit small intestine for testing drug absorption potency through the enterocyte's apical membrane, which is an important compartment for drug oral absorption. Some modifications have been made to the traditional vesicle assay for adapting it to the 96-well plate format. The accumulation of 23 reference drugs was measured, and the data showed a good correlation with human oral absorption with a correlation coefficient R=0.853 (P<0.001), with the exception of a few false positive results. As the measured drug absorption may contain a membrane/protein binding component as well as drug uptake into vesicles, these two fractions can be discriminated by changing extravesicular osmolarity using different mannitol concentrations. This model can be applied for evaluating drug absorption rate/mechanisms, and helping drug selection in early drug research and development.