title: Small molecule antagonists of the gonadotropin-releasing hormone (GnRH) receptor: structure-activity relationships of small heterocyclic groups appended to the 2-phenyl-4-piperazinyl-benzimidazole template.
abstract: A previous report described the serum LH suppression pharmacology of the 2-phenyl-4-piperazinyl-benzimidazole N-ethyluracil GnRH receptor antagonist 1 following oral administration in rats. A series of small heterocycles were appended to the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole template in place of the N-ethyluracil. Two imidazole analogues, 32 and 41, were shown to possess substantial in vitro potency at the target receptor (hGnRH IC(50) = 7 and 18 nM, respectively) and aqueous solubility (55 and 100 microg/mL at pH 7.4, respectively). Both compounds had high oral bioavailability in rats and 32 was further examined in an orchidectomized rat model for serum LH suppression based on increased volume of distribution over 41. Serum LH levels trended lower in orchidectomized rats following oral administration of 32.
authors.affiliation: Department of Chemical Sciences, Wyeth Research, 500 Arcola Rd., Collegeville, PA 19426, USA. hauzed@wyeth.com
authors.forename: Diane B
authors.initials: DB
authors.lastname: Hauze
authors.forename: Murty V
authors.initials: MV
authors.lastname: Chengalvala
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Cottom
authors.forename: Irene B
authors.initials: IB
authors.lastname: Feingold
authors.forename: Lloyd
authors.initials: L
authors.lastname: Garrick
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Green
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Wenling
authors.initials: W
authors.lastname: Kao
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kees
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Lundquist
authors.forename: Charles W
authors.initials: CW
authors.lastname: Mann
authors.forename: John F
authors.initials: JF
authors.lastname: Mehlmann
authors.forename: John F
authors.initials: JF
authors.lastname: Rogers
authors.forename: Linda
authors.initials: L
authors.lastname: Shanno
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Pelletier
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D007986:Luteinizing Hormone / Q000097:blood; D023421:Models, Animal; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D006571:Heterocyclic Compounds; D010879:Piperazines; D011966:Receptors, LHRH; D007986:Luteinizing Hormone