Derivatives 29a Methylpropylamide PK profile m Owned activity t in tests of gene linkage and a journalist. However, unlike benzylpyrazole showed compounds 4, 29a inhibitory activity of t against LNCaP PSA secretion hours reduced at high concentrations. On the other hand, morpholine derivative 29b showed increased Hte inhibitory activity of t-PSA in LNCaP h The pharmacokinetic profile of 29b was not as good as that of 29a. In view of the pharmacokinetic profile of compounds a good, we also studied the replacement of the fraction with phenyloxy heteroaryloxy group.31 The results for compounds 44a, 44b and 45 are shown in Table 4. None of these compounds showed agonistic activity t in a bid to the wild-type or mutated AR to move. 2 yloxy pyridine compounds 44a and 44b show moderate pharmacokinetic profiles. 44b survivin compound had moderate affinity t and antagonistic activity of t. It should be noted that 44a and 44b are strong inhibitory activity t against LNCaP showed PSA secretion Clock. Yloxy 45 pyridin compound 3 showed an hour Binding affinity here T and antagonistic activity Th, 44 were. In addition, the pharmacokinetic profile of pyridine compounds yloxy 2 better than that of the compounds pyridin yloxy third The AUC was 44 in the cassette dosing of mice M About 100 times larger It as the 45th of Based on these results, 44b hlt selected for further evaluation. We investigated the antitumor effects of 28h, 44b, and bicalutamide in mouse xenograft model with LNCaP cells h bicalutamide is reported that long term plasma concentrations at M to nnern Show. Long duration was also at M Observed mice. Based on these data for bicalutamide and pharmacokinetic data for 28h and 44b, these compounds were administered orally once or twice t Resembled administered for 4 weeks. The tumor volume and plasma PSA levels were measured after treatment. As shown in FIGS. 4 and 5 show compounds 28h and 44b very strong inhibition of tumor growth with T / C values of 3% and 2% at doses of 40 and 50 mg / kg, the supply, respectively. Plasma concentrations of PSA in these treatment groups were also significantly reduced by 23% and 17% of respondents in treatment groups of vehicles, respectively. Furthermore, these compounds have entered Born almost no loss of K Body weight. In addition, bicalutamide
showed partial suppression of tumor growth and had almost no effect on plasma PSA, even at a dose of 100 mg / kg, qd. These results, as wellin the course of the investigation of the new generation AR antagonists therapeutically effective con against the CRPC, we U, synthesized and evaluated the activity Th an arylmethyl phenylpyrazole 4 and 4, an aryloxy phenylpyrazole compounds B. In Figure 4, arylmethyl derivative reduces the introduction of a big s amide group in the 4 position of the benzyl group with a given 28h significant agonist activity t and improved pharmacokinetics. In Figure 4, aryloxy derivatives, the introduction of a voluminous Sen substituents at position 4 of the aryloxy group and replacement of the fraction with a phenyloxy pyridyloxy given improved pharmacokinetics and 44b. The oral administration of 28h and 44b induced extremely potent anti-tumor effect against the LNCaP h, a model of CRPC, in a xenograft mouse. In addition, administration of bicalutamide caused only partial suppression of the growth of LNCaP cells h was specified.