Synthesis and structure-activity relationships of novel benzimidazole and imidazo[4,5-b]pyridine acid derivatives as thromboxane A2 receptor antagonists.
A series of 1-benzylbenzimidazole and 3-benzylimidazo[4,5-b]pyridine substituted in the 2-position by an alkanoic or mercaptoalkanoic acid chain was synthesized for evaluation as potential thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists. The affinity of each compound for washed human platelet TXA2/PGH2 receptors was determined by radioligand binding studies using [125I]PTA-OH. Structure-activity relationships led to the conclusions that 2-alkanoic acid derivatives were slightly more potent than 2-mercaptoalkanoic acids and that compounds possessing a 3,3-dimethylbutanoic acid in the 2-position were definitely the most potent with Ki values of 4-39 nM (11a, 11g-x, 37a, 37f-o, 23a-c). The replacement of this 3,3-dimethylbutanoic acid side chain by a shorter one led to a marked decrease of affinity (11b and 11c; Ki = 5600 and 1700 nM, respectively). Compounds of benzimidazole and imidazo[4,5-b]pyridine series displayed similar potencies (11q and 23c have Ki values of 6 and 7 nM, respectively). The interesting pharmacological profile of compound 23a (UP 116-77: 4-[3-[(4-chlorophenyl)methyl]-6-chloroimidazo[4,5-b]pyridin-2-yl]- 3,3-dimethylbutanoic acid) and its excellent tolerance led us to select this derivative for further development.
Nicolaï
E
E
Carpibem, Rueil Malmaison, France.
Goyard
J
J
Benchetrit
T
T
Teulon
J M
JM
Caussade
F
F
Virone
A
A
Delchambre
C
C
Cloarec
A
A
D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D007093:Imidazoles; D011687:Purines; D011725:Pyridines; D017482:Receptors, Thromboxane; C081107:UP 116-77; C064191:1H-imidazo(4,5-b)pyridine