Design, synthesis and structure-affinity relationships of 4-methylidenepiperidine and 4-aryl-1,2,3,6-tetrahydropyridine derivatives as corticotropin-releasing factor(1) receptor antagonists

Recently, various non-peptide corticotropin-releasing factor(1) (CRF1) rece ptor antagonists have been reported. Structure-affinity relationships (SARs ) of non-peptide CRF1 antagonists suggest that such antagonists can be cons tructed of three units: a hydrophobic unit (Up-Area), a proton accepting un it (Central-Area), and an aromatic unit (Down-Area). Our interest focused o n the Up-Area in deriving the novel methyldenepiperidine derivatives 8-10 a nd 4-aryl-1,2,3,6-tetrahydropyridine derivatives 11-13 as non-peptide CRF1 receptor antagonists. Compounds 8a and 11a had moderate affinity for CRF1 r eceptor, but compounds 9, 10, 12 and 13 did not exhibit CRF1 receptor affin ity. Modification of derivatives 11 afforded compounds 11i (CRA1001) and 11 x (CRA\1000), which had high affinity and selectivity for CRF1 receptors wi th potent anxiolytic-like and antidepressant-like properties in some experi mental animal models. These findings suggest that the hydrophonic unit (Up- Area) may be useful for design of CRF1 antagonists. We report here the desi gn, synthesis and SARs of the derivatives 8 and 11 and isostens 9, 10, 12 a nd 13. (C) 2000 Elsevier Science Ltd. All rights reserved.