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.
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.
Hauze
Diane B
DB
Department of Chemical Sciences, Wyeth Research, 500 Arcola Rd., Collegeville, PA 19426, USA. hauzed@wyeth.com
Chengalvala
Murty V
MV
Cottom
Joshua E
JE
Feingold
Irene B
IB
Garrick
Lloyd
L
Green
Daniel M
DM
Huselton
Christine
C
Kao
Wenling
W
Kees
Kenneth
K
Lundquist
Joseph T
JT
Mann
Charles W
CW
Mehlmann
John F
JF
Rogers
John F
JF
Shanno
Linda
L
Wrobel
Jay
J
Pelletier
Jeffrey C
JC
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
D001562:Benzimidazoles; D006571:Heterocyclic Compounds; D010879:Piperazines; D011966:Receptors, LHRH; D007986:Luteinizing Hormone