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

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 1 (rCRF K-i = 44 nM) afforded no detectable rat plasma levels after intraperitoneal tip) or oral (po) dosing, compounds 3-3 (rCRF K-i = 16 nM) and 3-3 (rCRF K-i = 59 nM) gave high rat plasma levels at 30 mg/kg (ip po) (C-max = 1389 nM and 8581 nM tip) respectively; C-max = 113 nM and 988 nM (po), respectively). Furthermore 3-3 and 3-4 had superior bioavailabilities at these doses (59 and 46% (ip), respectively: 2 and 10% (po), respectively). (C) 1999 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.