1,4-Dihydropyridines as antagonists of platelet activating factor. 1. Synthesis and structure-activity relationships of 2-(4-heterocyclyl)phenyl derivatives

Abstract

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-[4-(2- methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2- pyridyl)carbamoyl]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 greater than 24 h following a single oral dose of 75 micrograms/kg) and was highly selective as a PAF antagonist, showing only weak affinity (IC50 = 6600 nM) for the [3H]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.

Diethyl 2,6-dimethyl-4-p-tolyl-1,4-dihydropyridine-3,5-dicarboxylate

“…Some DHPs have been introduced as neuroprotectants and cognition enhancers. In addition, a number of DHPs with platelet anti-aggregatory activity have also been discovered (Cooper et al, 1992).…”

“…For general background and applications of 1,4-dihydropyridine derivatives, see: Bö cker & Guengerich (1986); Cooper et al (1992); Vo et al (1995); Gaudio et al (1994); Gordeev et al (1996); Sunkel et al (1992). For ring conformations and ring puckering analysis, see: Boeyens (1978); Cremer & Pople (1975).…”

Microwave Assisted Fast Synthesis of CuO Nanoflakes: Catalytic Application in the Synthesis of 1,4-Dihydropyridine

“…These compounds were also found as potential calcium channel blockers in medicinal and bioorganic chemistry [22] and NADH models [23], respectively. Moreover, the 1,4-dihydropyridines also acts as a flexible intermediate in the synthesis of natural products owing to their higher reactivity [24].…”

Unambiguous structural assignment of monoanils of 3,4-pyridinedi- amine via regioselective synthesis

“…3,4-Diaminopyridine derivatives possess a wide range of biological activities [1][2][3][4] such as antiviral 5 , rodenticidal 6 , antimicrobial 7 , cytotoxic 8 , anti-osteoporosis and protein kinase C inhibitor 9 activities. The condensation of 2,3-pyridinediamine with carbonyl compounds 10,11 and their derivatives [12][13][14] has been studied previously.…”