Paf binding sites

Robaut, C.; Durand, G.; James, C. J.; Lavé, D.; Sédivy, P.; Floch, Anne; Mondot, S.; Pacot, Daniel; Cavero, Icilio; Fur, G. Le

doi:10.1016/0006-2952(87)90637-x

Cited by 21 publications

(2 citation statements)

References 17 publications

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“…results from attaching a 3-chlorophenyl ring onto the pyrrolothiazolidine RP-48,740 (platelet aggregation IC50 = 3300 nM)26 to give RP-52,770 (pA2 = 7.71 nM), 27 despite the fact that both compounds possess the carbonyl group necessary to satisfy the model. An overlay of RP-52,770 with compound 13 (modeled using Sybyl; see Figure 4) suggests how the pyridine and imidazopyridine rings can overlap sp'2 nitrogens, and although the nature of the linker groups is very different, nevertheless the 3-chlorophenyl and dichlorophenyl rings occupy a similar region of space.…”

Section: Resultsmentioning

confidence: 99%

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Novel Antagonists of Platelet-Activating Factor. 1. Synthesis and Structure-Activity Relationships of Benzodiazepine and Benzazepine Derivatives of 2-Methyl-1-phenylimidazo[4,5-c]pyridine

Mj¹,

Cooper²,

Mj³

et al. 1995

J. Med. Chem.

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Following the discovery of moderately potent antagonist activity platelet-activating factor (PAF) in 2-methyl-1-phenylimidazo[4,5-c]pyridine (2) (IC50 = 840 nM), 19 derivatives (3-21) were prepared which incorporated various lipophilic groups attached to the phenyl 4-position. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. [1,5]Benzodiazepines, e.g., 14 (2,3-dihydro-1-methyl-4-[4-(2-methylimidazo[4,5-c] pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-one) (IC50 = 4.9 nM, Ed50 = 0.03 mg/kg po), were found to possess equivalent or superior potency to the 1,4-dihydropyridine PAF antagonist UK-74,505 (1,4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2- [4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2-pyridyl) carbamoyl]pyridine) in vitro and in vivo. Furthermore, a potent benzazepine, 21 (7,8-dichloro-1-methyl-4-[4-(methylimidazo[4,5-c]pyrid-1-yl) phenyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one) (IC50 = 0.5 nM, ED50 = 0.03 mg/kg po), was discovered. These investigations prompted the synthesis and evaluation of additional diazepine derivatives, which are described in the following paper. The relationship between the key PAF antagonist pharmacophores of 2-methyl-1-phenylimidazo[4,5-c]pyridine, a triazolothienodiazepine (WEB2170), and a pyrrolothiazolidine (RP-52,770) is discussed.

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Section: Resultsmentioning

confidence: 99%

“…A solution of 26 (1.2 g, 3.2 mmol) in hydrochloric acid (2 M, 30 mL) was heated at reflux for 3 h, cooled, and concentrated under reduced pressure to give 2-amino[4-(2-methylimidazo-[4,5-c]pyrid-l-yl)phenyl]ethanone hydrochloride (27) as a colorless foam (1.35 g, >100%).…”

Section: -Aminomentioning

confidence: 99%