Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids.

A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids.

Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 2. Derivatives of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic (-heptanoic) acids.

A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.

Effects of leukotriene C4 on pancreatic secretion and circulation in dogs.

In the present study the effects of leukotriene C4 (LTC4) on exocrine pancreatic secretion and pancreatic blood flow were determined. LTC4 given intravenously in various doses ranging from 0.35 to 2.8 nmol.kg-1.h-1 in conscious dogs caused a dose-dependent inhibition of pancreatic HCO-3 and protein responses to exogenous hormones such as secretin, cholecystokinin octapeptide (CCK-8), and bombesin and to endogenous stimulants including meat feeding and duodenal perfusion with oleate. In tests with pancreatic secretion induced by secretin plus CCK, maximal inhibition by LTC4 occurred at a dose of 1.4 nmol.kg-1.h-1 and reached approximately 70% of the control value for HCO-3 output and 45% for protein output. In tests with separate secretin- or CCK-induced secretion, maximal inhibition occurred at a dose of 1.4 nmol.kg-1.h-1 and reached 38 and 66% of the control HCO-3 and protein secretion, respectively. The same dose of LTC4 reduced the postprandial HCO-3 secretion by approximately 80% and protein output by approximately 70%. After administration of indomethacin, the pancreatic secretion declined, but the inhibitory effects of LTC4 remained unchanged. Pancreatic tissue generated two to three times more LTC4 than the gastrointestinal mucosa, and indomethacin caused further increase in this generation, suggesting that LTC4 may contribute to indomethacin-induced pancreatic inhibition. (ABSTRACT TRUNCATED AT 250 WORDS)

Effects of leukotrienes on gastric acid and alkaline secretions.

This study was designed to determine the influence of leukotriene C4 on gastric acid and alkaline secretion. Leukotriene C4 was found to be a potent inhibitor of gastric acid secretion induced in vagally innervated and denervated portions of the stomach of conscious dogs by a variety of stimulants such as histamine, pentagastrin, and meat feeding. Leukotriene C4 was also an effective inhibitor of acid formation in the isolated gastric glands stimulated by histamine or dibutyryl cyclic adenosine monophosphate without or with addition of indomethacin, indicating that this compound acts directly on the parietal cells without mediation of endogenous prostaglandins. Leukotriene C4 was also an effective stimulant of gastric alkaline secretion. However, this effect was probably mediated by an increase in the generation of endogenous prostaglandin, as it was accompanied by an increase in the luminal release of prostaglandin E2 and indomethacin prevented both the stimulation of alkaline secretion and luminal prostaglandin E2 release by leukotriene C4.