A series of benzimidazole-based analogues of the potent MTP inhibitor BMS-201038 were discovered. Incorporation of an unsubstituted benzimidazole moiety in place of a piperidine group afforded potent inhibitors of MTP in vitro which were weakly active in vivo. Appropriate substitution on the benzimidazole ring, especially with small alkyl groups, led to dramatic increases in potency, both in a cellular assay of apoB secretion and especially in animal models of cholesterol lowering. The most potent in this series, 3g (BMS-212122), was significantly more potent than BMS-201038 in reducing plasma lipids (cholesterol, VLDL/LDL, TG) in both hamsters and cynomolgus monkeys.
By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)
6-Methoxy-3-(3′,4′,5′-trimethoxy-benzoyl)-1H-indole (BPR0L075) is a novel synthetic indole compound with microtubule binding activity. Incubation of BPR0L075 with mouse, rat, dog, and human liver microsomes in the presence of NADPH resulted in the formation of six metabolites. Liquid chromatography-tandem mass spectrometry and comparison with the synthetic reference standards identified two metabolites (M1 and M5) as the products derived from hydroxylation on the indole moiety of the molecule. M3 was also identified as a product derived from hydroxylation, but the structure of this metabolite was not identified because of the lack of a reference standard. M2, M4, and M6 were identified as the products derived from O-demethylation. M2, 6-desmethyl-BPR0L075, was the major metabolite formed by the liver microsomes of the four species. No qualitative species difference in the metabolism of BPR0L075 was observed. There was quantitative species difference in the metabolism of BPR0L075 among the four species. Whereas mouse and rat liver microsomes metabolized BPR0L075 predominantly via O-demethylation, dog liver microsomes metabolized BPR0L075 by O-demethylation and hydroxylation to about the same extent. The rank order of intrinsic clearance rates for the conversion of BPR0L075 to 6-desmethyl-BPR0L075 was mouse > rat > human > dog. Incubation of BPR0L075 with baculovirus-insect cell-expressed human cytochrome P450 (P450) isozymes showed that CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 all catalyzed the O-demethylation and hydroxylation of BPR0L075 but to a different degree. Among the six P450 isozymes tested, CYP1A2 and 2D6 were most active on catalyzing the metabolism of BPR0L075. CYP1A2 catalyzed mainly the formation of M1, M2, and M3. M2 was the predominant metabolite formed by CYP2D6.
Abstract In contrast to human erythrocytes, rat erythrocytes synthesize NAD directly from nicotinamide via NMN. 14C from nicotinamide appeared in NMN and NAD and to lesser extent in nicotinamide ribonucleoside and NADP. Mono- and dinucleotides formed were present solely within the cells, whereas nucleosides and the unchanged substrates readily passed through the cell membrane. NMN pyrophosphorylase, the first enzyme of this pathway, has been purified about 400-fold from rat erythrocytes and was shown to require ATP and Mg++, to have a pH optimum of 8.5 to 9.0 and to have Km values of 0.067 and 3.8 µm for nicotinamide and PP-ribose-P, respectively. The enzyme activity was increased 50% in the presence of 1 mm EDTA. Although NMN pyrophosphorylase cannot be measured in a buffer system of pH 7.4, due to the hydrolysis of the product by NAD glycohydrolase in the hemolysate, it can be readily measured at pH 8.8 where NAD glycohydrolase is not active. From radioactive nicotinic acid the major labeled products were nicotinic acid ribonucleotide, nicotinic acid ribonucleoside, and NAD with lesser amounts of label in nicotinic acid adenine dinucleotide and nicotinamide. The results suggest that nicotinic acid is converted to NAD by the Preiss-Handler pathway while nicotinamide is metabolized via the parallel pathway through NMN.
In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.
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