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
Mj. Fray et al., 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, Journal of medicinal chemistry, 38(18), 1995, pp. 3514-3523
Following the discovery of moderately potent antagonist activity again
st platelet-activating factor (PAF) in 2-methyl-1-phenylimidazo[4,5-c]
pyridine (2) (IC50 = 840 nM), 19 derivatives (3-21) were prepared whic
h incorporated various lipophilic groups attached to the phenyl 4-posi
tion. Structure-activity relationships were evaluated where PAF antago
nist activity was measured in vitro by determining the concentration o
f compound (IC50) required to inhibit the PAF-induced aggregation of r
abbit washed platelets and in vivo by determining the oral dose (ED(50
)) which protected mice from a lethal injection of PAF. [1,5]Benzodiaz
epines, e.g., 14 -c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-one) (I
C50 = 4.9 nM, ED(50) = 0.03 mg/kg po), were found to possess equivalen
t or superior potency to the 1,4-dihydropyridine PAF antagonist UK-74,
505 (1, idazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2-pyridyl)car bamoyl]pyri
dine) in vitro and in vivo. Furthermore, a potent benzazepine, 21 )phe
nyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one) (IC50 = 0.5 nM, ED(50)
= 0.03 mg/kg po), was discovered. These investigations prompted the sy
nthesis 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.