Affinity. With high binding affinity t, showed antagonistic activity of compound 4a t compared to wild type, mutant-type T877A, W741C and AR agonistic activity mutant with no significant t. In compound 4a, the bcl-2 replacement of the benzene ring with a cyclohexane ring reduced activity t. For the linker X, ethylene, carbonyl, sulfonyl, and showed activity t less effective than methylene. These results indicate that a terminal aromatic R1 and X-linker methyl group were positive for C. Thus, w We hlten a four arylmethyl compounds phenylpyrrole 4 for a further study, and a review R1 to R5, as shown in Table 2. We investigated the requirement of an electron withdrawing group on the aromatic ring to R4, and found that a cyano group resembled tolerated For antagonist activity t was. The removal of the nitro group or a cyano group reduced activity t. It was reported that a nitro or cyano group is primarily for the ligand binding AR binding domain.35 The importance of these groups in our study were required. Used introducing a trifluoromethyl group at position 3 of 4 cyanophenyl fragment Born agonistic activity of t against the AR T877A mutant. the substituents R3 assessment igf-1r leads replacing the ester moiety with a cyano group to a significant Erh increase the binding affinity t and antagonist activity of t. However, decreased
a carboxy group, a hydroxymethyl group, an acetyl group or activity T. 4f compound, the absence of a substituent at position 3 of pyrrole showed a reduced activity of t against the W741C mutant AR type. Replacing the benzene ring R1 with other aromatic heterocyclic compounds have been studied to the L To improve solubility. 4d compounds showed a high binding affinity t and antagonistic activity of t, but had a low L Solubility. Improving the solubility L By replacing was the benzene ring with pyridine. Compound 4k showed a strong affinity t and antagonistic activity of t compared to wild type, mutant-type T877A, W741C and AR-mutant type. However, a weak agonist activity t was observed. As described above, with minimal agonist activity t is important to the effectiveness against computer, including normal PCs castration. We found that the introduction of substituents in the pyridine ring, the agonistic activity 4k t decreases observed. Significantly, 4n and chlorine compounds hydroxymethylgroup on the pyridine ring, showed a strong antagonistic activity T ladle and a further increase Increase of L Solubility. The Erh Increase of L Solubility observed for chloropyridine 4l and 4m pyridine. Thus, a combination of a chlorine and a hydroxymethyl group on the pyridine ring, both physical and biological properties favorable. Closing HA-1077 We have, R2 and R5 rated pyrrole skeleton. The elimination of the methyl group at either R2 or R5 4n, in particular R2, antagonist activity Reduced t, indicating that both R2 and R5 are methyl groups for antagonistic activity of t. Based on these biological and physical profiles, w We hlten 4n compounds for further evaluation. 4n compound was orally available in mice M. 4n compound was obtained in its effect on reducing the weight of the ventral prostate in M Nozzles in comparison with intact bicalutamide evaluated. This test simulates a single agent in hormone-dependent Ngigen PCs.36 as sh.