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    • Next we focused on B part the phthalazine ring While

    2022-05-25

    Next, we focused on B-part, the phthalazine ring. While both nitrogen atoms of the phthalazine ring were found to be important (data not shown), replacing the benzene ring of the phthalazine part was attempted, and shows the results of the substituted pyridazine rings with bearing 2-methoxy benzene at A-part toward specific activities against at 30 μM. The cyclohexyl ring () drastically deteriorated the GLUT4 translocation activity, whereas cyclopentyl ring () improved the activity by almost two times compared to . As for the other non-cyclic alkyl moiety, dimethyl group () was also acceptable, but less so than , while diethyl group () resulted in a loss of activity. These results indicated that the acceptable space around the central benzene ring should be strictly limited and the five-membered ring seemed to be favorable. Based on these results, in-depth studies regarding the central ring were conducted to explore the possibility of other ring groups besides the cyclopentyl group (). The SAR of the central ring toward the specific GLUT4 translocation activity at 3 μM compared to the activity of at 30 μM is also summarized in . Reference 73122 exhibited an activity at 3 μM 0.39 times that at 30 μM. There are slight differences between the two furan compounds ( and ), but both were acceptable. On the other hand, the substitution at the 2-position of the furan ring () dispersed the activity, suggesting the limited space around the central benzene ring as mentioned above. Among the aryl rings, thiophene ( and ) was superior and, in particular, 3-thienopyridazine compound presented the best result. The activity of at 1 μM was almost the same as at 30 μM, which means that compound had a 30-fold increase of activity compared to . Subsequently, C-part, phenyl acetic amide, was explored. In this derivatization study, we selected the cyclopentyl moiety as the central ring and the specific active values at 3 μM as a result of replacing C-prat are summarized in . The mono- and di-methyl amide worsened the activity ( and ), meaning that the two protons of the amide moiety were important. The change of the length of the methylene linker between the phenyl and amide moiety, such as and , or the position of the acetic amide moiety attached to the benzene ring, such as , resulted in an unfortunate consequence. These results suggest that the length and the relative position between the amide moiety and phenyl ring was very important. The introduction of the dimethyl or the cyclopropyl moiety on the methylene position was acceptable ( and ). Sulfonamide group () as a mimetic of the amide group was also found to be disfavored. Conversion from the benzene ring to hetero-aromatic rings, such as pyridine, pyrimidine or thiazole ring, caused GLUT4 activities to disappear (data not shown). Consequently, the original phenyl acetic amide from our cell-based phenotype screening was found to be the best substituent group. Next, the suitable substitutions of the benzene ring of C-part were explored, and their specific activities at 3 μM compared to are summarized in . Between the 2- and 3-position, the 2-position was more favorable according to the results of the methyl and fluoro substitutions (, vs. , ). The chloro group () was also acceptable, but others at the 2-position, such as methoxy (), hydroxy (), and trifluoromethyl () groups, reduced the activities. As a result, 2-F () gave the best result, greater by a factor of about two, compared to . The results of the above studies suggest that 3-thioenopyridazine as B-part and 2-F phenyl acetamide as C-part were found to be the most favorable units. Using these results, another attempt at optimizing A-part was conducted, focusing on the ether moiety on the benzene ring, and the EC values in addition to their logD results and the liver microsomal stabilities in mouse are summarized in . Thiophene compound had more potent activity, and the EC value was 0.65 μM, almost seven times greater than the cyclopentyl counterpart (, EC = 4.7 μM). The length of the substituent at the 2-position was found to be important for the activity, and the chain ( or , which is longer than methoxy group (), resulted in a good effect. As for the substituents at the 2-position, it was surprising that the replacement of the terminal methoxy moiety of to the NHBoc group () drastically improved the activity (EC =0.024 μM).