title: Structure-activity studies on 4-substituted-2-anilinopyrimidine corticotropin releasing factor (CRF) antagonists.
abstract: 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 Ki = 44 nM) afforded no detectable rat plasma levels after intraperitoneal (i.p.) or oral (p.o.) dosing, compounds 3-3 (rCRF Ki = 16 nM) and 3-4 (rCRF Ki 59 nM) gave high rat plasma levels at 30 mg/kg (i.p., p.o.) (Cmax = 1389 nM and 8581 nM (i.p.) respectively; Cmax = 113 nM and 988 nM (p.o.), respectively). Furthermore 3-3 and 3-4 had superior bioavailabilities at these doses (59 and 46% (i.p.), respectively; 2 and 10%, (p.o.), respectively).
authors.affiliation: DuPont Pharmaceuticals Company, Department of Chemical and Physical Sciences, Experimental Station, Wilmington, DE 19880-0500, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Gilligan
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: S
authors.initials: S
authors.lastname: Culp
authors.forename: L
authors.initials: L
authors.lastname: Fitzgerald
authors.forename: S W
authors.initials: SW
authors.lastname: Tam
authors.forename: Y N
authors.initials: YN
authors.lastname: Wong
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000814:Aniline Compounds; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone