6.54.5ONO8ROSOORNR1OONONOSONOROOOOOβδNαOOSHH4HH56HHN0.9%1.23.9>1,000223FFFHN3.42.84.72.22.4>1,0001450.7NHNHHN3.08.41.2>1,000300NH2.64.13.8>1,0007603.8>1,000300(% of Rif.)(% of Rif.)Table 2.Structure-activity relationship and CYP3A4 induction for 8-substituted analogsTable 3.SAR for 8-substituted analogsTable 4.SAR for Me scan on pyridine ringOOOOCompound2a2b2cCompound2c3a3b3cCompoundαβδ3c(CH7057288)MeHNH3.41.43.9>1,0002230.7MPRIP-NTRK1MPRIP-NTRK1MPRIP-NTRK1CYP3A4fold induction(vs DMSO)LCKNIH3T31005919053 501675CYP3A4fold induction(vs DMSO)LCKNIH3T375159678313014IC50(nM)NIH3T3LCK6001301465455.44.21.20.9%4.7CYP3A4relative induction33%26%11%CYP3A4relative induction11%11%12%CYP3A4fold induction(vs DMSO)CYP3A4relative induction(% of Rif.)12% 7% 7% 9%relativeinduction<20%を示し、CYP3A4誘導を有意に低下させた。さらに、化合物2cは1と比較してTRKA阻害活性、細胞増殖阻害活性およびTRKA選択性を維持できており、2cのTRKA阻害活性向上に向けた誘導体化に着手した。4. TRKA阻害活性向上とCH7057288の創製 ピリジン環上の置換基変換結果をTable3、4に示す3)。トリフルオロエトキシ基3aはTRKA阻害活性向上が確認されたが、細胞増殖阻害活性の改善はなかった。シクロプロピルアミド3bはTRKA阻害活性を約1.6倍向上119IC50(nM)TRKAKDR760690 290 IC50(nM)TRKAKDR997600TRKAKDRHMeHHMe
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