142161-48-6Relevant articles and documents
1,4-Dihydropyridines as Antagonists of Platelet Activating Factor. 1. Synthesis and Structure-Activity Relationships of 2-(4-Heterocyclyl)phenyl Derivatives
Cooper, Kelvin,Fray, M. Jonathan,Parry, M. John,Richardson, Kenneth,Steele, John
, p. 3115 - 3129 (2007/10/02)
A novel class of 2-(4-heterocyclylphenyl)-1,4-dihydropyridines (2-38) possessing antagonist activity against platelet activating factor (PAF) was prepared by the Hantzsch synthesis from a variety of ethyl 4'-heterocyclic-substituted benzoylacetates, aryl or heteroaryl aldehydes, and substituted 3-aminocrotonamides or 3-aminocrotonate esters.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.The nature of the substituent at the dihydropyridine 2-position was found to be important for both in vitro and in vivo activity, whereas there was greater flexibility for structural variation at the 4- and 5-positions.The most potent compound was 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2-pyrid-1-yl)phenyl>-5-pyridine (17, UK-74,505), IC50 = 4.3 nM, ED50 = 0.26 mg/kg po, which was found to be approximately 33 times more potent in vitro (rabbit platelet aggregation) and about 8 times more potent in vivo (murine lethality) than WEB2086.Compound 17 also exhibited a long duration of action in the dog (inhibition of PAF-induced whole blood aggregation ex vivo was maintained for > 24 h following a single oral dose of 75 μg/kg) and was highly selective as a PAF antagonist, showing only weak affinity (IC50 = 6600 nM) for the nitrendipine binding site.As a result of its high oral potency, selectivity, and duration of action, UK-74,505 has been selected for clinical evaluation.
Platelet activating factor antagonists
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, (2008/06/13)
Platelet activating factor antagonists of formula (I): STR1 wherein R is phenyl or phenyl substituted by one or more substituents selected from nitro, halo, C1 -C4 alkyl, C1 -C4 alkoxy, aryl (C1 -C4) alkoxy, fluoro (C1 -C4) alkoxy, C1 -C4 alkylthio, C1 -C4 alkylsulphonyl, hydroxy, trifluoromethyl and cyano, or is phenyl fused to a dioxole ring; R1 and R2 are each independently H or C1 -C6 alkyl, or R1 and R2 together complete a pyrrolidinyl, piperidino, morpholino, piperazinyl, N-(C1 -C4 alkyl) piperazinyl or N-(C2 -C4 alkanoyl)-piperazinyl group; or R2 is H or C1 -C4 alkyl and R1 is CN, C3 -C7 cycloalkyl, aryl, heteroaryl or a C1 -C4 alkyl group substituted by one or more substituents selected from C3 -C7 cycloalkyl, C1 -C4 alkoxycarbonyl, aryl or heteroaryl; Z is selected from C1 -C6 alkoxy, aryl (C1 -C4) alkoxy, hydroxy, and --NR4 R5 wherein each of R4 and R5 is independently H or C1 -C6 alkyl, or R4 and R5 together complete a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1 -C4 alkyl) piperazinyl group; Y is 1,4 phenylene or pyridine-2,5-diyl, and X is a 5 or 6 membered aromatic heterocyclic group containing one or more nitrogen atoms in its ring; which ring may be fused to a benzene ring or to a further 5- or 6-membered aromatic heterocyclic ring containing one or more nitrogen atoms, at least one of said heterocyclic rings optionally also containing an oxygen or sulphur atom, and being optionally substituted with one or more substituents selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3 and CN; and their pharmaceutically acceptable salts.
