Structure–activity studies on 4-substituted-2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists Original Research Article

Structure–activity studies around the 4-position of 2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists suggest that there is a large lipophilic cavity in the rat CRF receptor, which can accommodate a wide variety of substituents at this position in contrast to the steric constraints observed for other positions on the 2-anilinopyrimidine core. The chemical syntheses and biological activities of 2-anilinopyrimidine CRF antagonists with carbon-linked substituents at the 4-position are reported. Significant improvements in rat pharmacokinetic parameters were achieved relative to those for the lead structure. While the lead compound (rCRF Ki=44 nM) afforded no detectable rat plasma levels after intraperitoneal (ip) or oral (po) dosing, compounds - (rCRF Ki=16 nM) and -4 (rCRF Ki=59 nM) gave high rat plasma levels at 30 mg/kg (ip, po) (Cmax=1389 nM and 8581 nM (ip) respectively; Cmax=113 nM and 988 nM (po), respectively). Furthermore - and -4 had superior bioavailabilities at these doses (59 and 46% (ip), respectively; 2 and 10% (po), respectively).