Synthesis and biological evaluation of substituted benzenesulfonamides as novel potent membrane-bound phospholipase A2 inhibitors

Abstract

A novel series of 4-[N-methyl-N-[(E)-3-[4-(methylsulfonyl)phenyl]-2- propenoyl]amino]benzenesulfonamides has been prepared and evaluated as membrane-bound phospholipase A2 inhibitors. A structure-activity relationship study indicated that the optimum potency was realized with the N-(phenylalkyl)piperidine derivatives 3 and 4. These compounds inhibited the liberation of arachidonic acid from the rabbit heart membrane fraction with IC30 values of 0.028 and 0.009 microM, respectively. Several compounds (3, 4, and 28), which proved to be potent inhibitors in vitro, significantly reduced the size of myocardial infarction in coronary occluded rats by iv administrations prior to the ligation. N-(1-Benzyl-4-piperidinyl)-4-[N-methyl-N-[(E)-3-[ 4-(methylsulfonyl)phenyl]-2-propenoyl]amino]-benzenesulfonamide (3, ER-3826), which showed the protective in vivo effects at doses higher than 0.3 mg/kg iv, was finally chosen as a leading candidate.

Phospholipase A2 Enzymes: Physical Structure, Biological Function, Disease Implication, Chemical Inhibition, and Therapeutic Intervention

“…135 Several compounds ( 12a,b ), which proved to be potent inhibitors in vitro, significantly reduced the size of myocardial infarction in coronary occluded rats by iv administrations prior to the ligation. Compound 12a (ER-3826), which showed the protective in vivo effects at doses higher than 0.3 mg/kg iv (Table 4), was finally chosen as a leading candidate.…”

“…Compound 12a (ER-3826), which showed the protective in vivo effects at doses higher than 0.3 mg/kg iv (Table 4), was finally chosen as a leading candidate. 135 …”

Inhibitors of Brain Phospholipase A2Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

“…3) and its piperidine derivative are the most potent inhibitors of membrane-bound heart PLA 2 activity with IC 50 values of 28.0 and 9.0 nM, respectively (Oinuma et al, 1991). Intravenous injections of these inhibitors protect rats against ischemic damage in acute myocardial infarction.…”

A New Nonpeptide Tachykinin NK1 Receptor Antagonist Isolated from the Plants of Compositae.

“…Thus, the acid chlorides 3a-g [8][9][10][11][12]) and 5 13) prepared from the corresponding carboxylic acids were condensed with spermine or its analogs to give the amides 4a-g, whose protecting groups were saponified with 1 N NaOH to afford 1a-d, g, 6, 10-12. The activities of these amides as tachykinin NK 1 receptor antagonists were estimated by their inhibitory actions on SP-induced contraction of the guinea pig ileum and by their competitive inhibition of the binding of [ Table 2.…”

“…The acid chlorides 3a, 8) 3b, 9) 3c, 10) 3d, 11) 3e, 12) and 5 13) were prepared from the corresponding carboxylic acids by the reported procedures. 3-Phenyl-2-propenoyl chloride (3f) was obtained from Aldrich.…”