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Biomedical subjects

H R Davis

Publications and source records attributed to H R Davis.

At least 19 recordsLinked to original sources
PubMed1998

Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption.

(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.

Animals↗
PubMed1998

Carboxy-substituted 2-azetidinones as cholesterol absorption inhibitors.

Metabolism initiated SAR studies led to the discovery of a new class of potent 2-azetidinone cholesterol absorption inhibitors. These studies found that a heteroatom at the para position of the C-4 phenyl ring is not a requirement for cholesterol absorption inhibition as was suggested by earlier findings. Substitution of Ph-linker-COOR for PhOMe at the C-4 position enhanced cholesterol absorption inhibition.

Animals↗
PubMed1998

Sugar-substituted 2-azetidinones as cholesterol absorption inhibitors.

The asymmetric synthesis of a glucuronide conjugate of the 2-azetidinone cholesterol absorption inhibitor Sch 48461 was accomplished to confirm the structure of a metabolite isolated from in vivo sources. Key features of this article include the asymmetric synthesis of 2-azetidinones by Evan's chiral oxazolidinone methodology and glucuronide formation by a Mitsunobu protocol.

Animals↗
PubMed1998

Effect of chronic central administration of glucagon-like peptide-1 (7-36) amide on food consumption and body weight in normal and obese rats.

Glucagon-like peptide (7-36) amide (GLP-1) acutely inhibits food and water consumption in rats after intracerebroventricular (icv) administration. To assess the potential for desensitization of these effects, we investigated the effects of chronic icv administration of GLP-1 on food consumption and body weight in Sprague-Dawley (SD) rats and Zucker (fa/fa) obese rats. In vitro functional densensitization of the GLP-1 receptor was not observed after overnight exposure of Rin m5F insulinoma cells to GLP-1 at concentrations up to 10 nM. Administration of GLP-1 to SD rats (30 microg icv twice a day for 6 days) resulted in significant reductions in 24-hour food consumption each day (25 +/- 1%). Continuous icv infusion of GLP-1 for 7 and 14 days significantly inhibited cumulative food consumption and reduced body weight in SD rats. In the genetically obese Zucker rat, chronic dosing with GLP-1 (30 microg icv) once a day for 6 days caused significant reductions in food consumption each day and a reduction in body weight. These results indicate that the GLP-1 pathways in the central nervous system controlling food consumption do not desensitize after chronic exposure to GLP-1 and suggest that agonists of the central GLP-1 receptor may be effective agents for the treatment of obesity.

Animals↗
PubMed1997

Diet-induced obese mice develop peripheral, but not central, resistance to leptin.

Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin.

Animals↗
PubMed1997

In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461.

SCH48461 is a selective and highly potent inhibitor of cholesterol absorption. In rats, SCH48461 is rapidly and completely metabolized in the first pass through the body. To compare the activity of the metabolites of SCH48461 with SCH48461 itself, an intestinally cannulated, bile duct-cannulated rat model for cholesterol absorption was developed. SCH48461 inhibited the absorption of cholesterol by 70%, whereas bile containing the metabolites of SCH48461 (henceforth, "metabolite bile") inhibited the absorption by greater than 95%. Very little of the recovered radioactive dose of SCH48461 was located in the intestinal lumen (7%) or wall (4%), whereas 85% appeared in bile. However, in rats treated with metabolite bile, 62% of the dose remained in the lumen, 13% was associated with the wall and only 24% reappeared in bile, which suggests that the activity of the metabolite bile may be related to its higher retention in the intestinal wall. Rats treated with metabolite bile had 64% and 84% less drug-related radioactivity in their plasma and livers, respectively, compared with animals treated with SCH48461, which indicates that the metabolites are systemically less available than SCH48461. The metabolites in bile were separated by high-performance liquid chromatography; the most active fraction in the bile duct-cannulated rat model was identified by mass spectrometry as the glucuronide of the C4-phenol of SCH48461. The other fractions had moderate or no activity. Through the identification of the most active biliary metabolites of SCH48461 in the rat, we have discovered SCH58235, a novel cholesterol absorption inhibitor which is 400 times more potent than SCH48461 in the cholesterol-fed rhesus monkey.

Absorption↗
PubMed1996

2-Azetidinone cholesterol absorption inhibitors: structure-activity relationships on the heterocyclic nucleus.

A series of azetidinone cholesterol absorption inhibitors related to SCH 48461 ((-)-6) has been prepared, and compounds were evaluated for their ability to inhibit hepatic cholesteryl ester formation in a cholesterol-fed hamster model. Although originally designed as acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, comparison of in vivo potency with in vitro activity in a microsomal ACAT assay indicates no correlation between activity in these two models. The molecular mechanism by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of the in vivo activity of a range of compounds has revealed clear structure-activity relationships consistent with a well-defined molecular target. The details of these structure-activity relationships and their implications on the nature of the putative pharmacophore are discussed.

Absorption↗
PubMed1996

The relationship of tissue localization, distribution and turnover to feeding after intraperitoneal 125I-leptin administration to ob/ob and db/db mice.

Brain and whole body localization and distribution of 125I-leptin was determined after intraperitoneal administration to ob/ob and db/db mice, and was compared to inhibition of food intake. Food intake was not significantly inhibited at3 hours post-injection, but was decreased significantly at 6 h (p < 0.0007) and 24 h (p < 0.02) in ob/ob mice, times at which > 97 % of the radioactive dose was found in the urine. The highest concentrations of 125I-leptin at all time-points were found in the serum, liver and kidneys. These findings were verified by whole body autoradiography. Virtually no 125I-leptin was found in the CNS at later timepoints in either ob/ob or db/db mice. Coronal sectioning of entire brains from ob/ob and db/db mice revealed 125I radioactivity localized to the choroid plexus and in the ventricular space, but not in other CNS regions. No differences in localization, accumulation, or clearance of 125I-leptin in ob/ob vs. db/db mice were found in any of the tissues studied. The present studies demonstrate that the inhibitory effect of leptin on food intake in the ob/ob mouse persists for up to 24 hours after a single dose, despite the complete degradation and elimination of the labeled leptin during the first several hours after injection.

Adipose Tissue↗
PubMed1995

Substituted (1,2-diarylethyl)amide acyl-CoA:cholesterol acyltransferase inhibitors: effect of polar groups on in vitro and in vivo activity.

Substituted (1,2-diarylethyl)amides have been prepared and evaluated for their ability to inhibit microsomal acyl-CoA:cholesterol acyltransferase activity in vitro and to lower hepatic cholesteryl ester content in vivo in a cholesterol-fed hamster. Simple unsubstituted (diarylethyl)amides were potent inhibitors in vitro but showed poor activity in vivo. Introduction of polar groups at specific locations on the diarylethylamine moiety decreased in vitro activity but increased in vivo activity. Both effects were highly structure dependent, suggesting specific interactions which were mediating activity in each model. Optimization of these opposing effects led to compounds which were potent in both models.

Amides↗
PubMed1995

Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461.

The amount of cholesterol that circulates in the plasma as lipoproteins can be affected by the balance of cholesterol metabolism within and between the intestines and liver. In the present report, we describe a novel hypocholesterolemic agent and document its pharmacological effects in animal models of hypercholesterolemia. The oral administration of (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone (SCH 48461) reduced plasma cholesterol concentrations in cholesterol-fed hamsters, rats and rhesus monkeys with ED50s of 1, 2 and 0.2 mg/kg per day, respectively, SCH 48461 was also highly effective in reducing hepatic cholesteryl ester accumulation in cholesterol-fed hamsters and rats after 7 days of treatment. In one 3 week study, rhesus monkeys were fed a 0.25% cholesterol/22% saturated fat diet with or without SCH 48461. At the end of the 3 week period the control group's VLDL + LDL-cholesterol increased to 180 Mg/dl from a baseline of approximately 65 mg/dl while plasma apolipoprotein B levels had doubled. Animals treated daily with 1 mg/kg SCH 48461 maintained their baseline levels of VLDL + LDL-cholesterol, HDL-cholesterol, and plasma apolipoproteins B and A-I. After 3 weeks the diets of the two groups were switched. Within 1 week SCH 48461 (1 mg/kg per day) rapidly reversed the elevated VLDL + LDL-cholesterol levels of the previous control group to near baseline values. SCH 48461 exerted its hypocholesterolemic effect through the inhibition of cholesterol absorption. A dose of 10 mg/kg per day inhibited cholesterol absorption in cholesterol-fed hamsters by 68% while a similar reduction was achieved in chow-fed monkeys with 3 mg/kg per day. This latter dose inhibited cholesterol absorption in cholesterol-fed monkeys by 95%. Treatment of cholesterol-fed monkeys with 10 mg/kg per day SCH 48461 significantly increased fecal neutral sterol excretion (52 vs. 32 mg/kg) but had no effect on acidic sterol excretion. Using a 2-h absorption model in cholesterol-fed hamsters, SCH 48461 caused a 46% inhibition of unesterified [14C]cholesterol accumulation in the intestinal wall and a 90% inhibition of cholesteryl ester formation at a dose of 10 mg/kg. Similar data were observed when the plasma radioactivity was assessed, indicating inhibition of both free (61%) and esterified (85%) cholesterol appearance. In contrast, CI-976, a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, did not affect the uptake of free cholesterol into the intestines while inhibiting cholesterol esterification (98% inhibition).(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1995

Amides of piperidine, morpholine and piperazine substituted 1-phenylethylamines: inhibitors of acylCoA:cholesterol acyltransferase (ACAT) activity in vitro and in vivo.

Amides of some substituted 1,2-diarylethylamines have been shown to exhibit potent acylCoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) inhibitory activity in vitro in microsomal ACAT assays but show poor in vivo activity in a cholesterol-fed hamster model. In an effort to design ACAT inhibitors that are potent in both our in vitro and in vivo assays a series of amides of piperidine, morpholine and piperazine substituted 1-phenylethylamines were synthesized. Compounds of this series were found to be very potent inhibitors of ACAT in a microsomal ACAT assay and also exhibited potent activity in a cholesterol-fed hamster model.

Amides↗
PubMed1995

The effect of acyl CoA: cholesterol acyltransferase inhibition on the uptake, esterification and secretion of cholesterol by the hamster small intestine.

Acyl CoA: cholesterol acyltransferase (ACAT) inhibitors are known to inhibit cholesterol absorption and are under investigation to reduce hypercholesterolemia. These studies examine the effect of an ACAT inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)-dodecanamide (PD128042) on the uptake, metabolism and secretion of cholesterol by the hamster intestinal wall in a short-term model. Preliminary studies in this model indicated that the uptake of 14C-cholesterol and its subsequent esterification 2 hr postoral dosing occurs primarily in the duodenal and jejunal segments of the small intestine and most of the radiolabeled cholesterol and cholesteryl ester in the plasma was associated with chylomicrons. In both single- and multiple-dose studies, PD128042 (50 mg kg-1 day-1) did not inhibit intestinal uptake of [14C]-cholesterol but [14C]-cholesteryl ester formation was inhibited. The free [14C]-cholesterol appearing in plasma was not affected despite a large reduction in [14C]-cholesteryl ester. In contrast, cholestyramine (1 g kg-1 day-1) inhibited the uptake of the radiolabeled free cholesterol and the appearance of cholesteryl ester in the intestine and plasma. The effects of PD128042 on cholesterol and cholesteryl ester mass associated with scraped intestinal mucosa were consistent with the effects observed with the use of the radiolabeled cholesterol. In addition, PD128042 did not affect the uptake of appearance of radiolabeled triglyceride in the intestinal wall after oral gavage of 3H-trioleoylglycerol. Taken together, the data suggest that ACAT inhibition reduces cholesterol absorption by limiting cholesteryl ester incorporation into chylomicrons and has no effect on the intestinal processing of free cholesterol to be secreted into plasma.

Anilides↗
PubMed1994

Demonstration of a direct effect on hepatic acyl CoA: cholesterol acyl transferase (ACAT) activity by an orally administered enzyme inhibitor in the hamster.

Orally active inhibitors of acyl CoA:cholesterol acyl transferase (ACAT), such as Lederle CL277082 (LE), are known to reduce plasma and hepatic cholesteryl ester levels, although the mechanisms are not well understood. Several groups have reported the inhibition of cholesterol absorption upon oral ACAT inhibitor administration. In this study, we used 7-day dietary and drug treatments of hamsters to examine the possible effects of LE on hepatic ACAT. ACAT assays were performed using liver homogenates in the absence and presence of a saturating level of exogenously added cholesterol. LE (100 mg/kg/day) treatment of chow or 0.5% cholesterol-fed animals caused reductions in ACAT activity without additional cholesterol as compared with non-treated animals. When a saturating level of cholesterol was added to the assays, reductions in ACAT activity upon LE treatment of chow- or cholesterol-fed animals were also observed. Treatment of cholesterol-fed animals with cholestyramine in the diet reduced ACAT activity in the absence of added cholesterol. However, ACAT activities similar to those of non-treated animals were observed at a saturating level of cholesterol. This latter effect demonstrates that inhibition of cholesterol absorption reduces cholesterol delivery to the liver but does not reduce cholesterol esterifying capacity since cholestyramine is not absorbed and has no direct effect on the liver. The decreased ACAT activity in homogenates from LE-treated animals could also be mimicked in a dose-dependent manner by the addition of exogenous LE to liver homogenates from non-treated animals. These results indicate that hepatic ACAT activity is regulated by the availability of free cholesterol, and that orally administered LE has a direct effect on hepatic ACAT activity in the liver. In addition, the data are consistent with LE activity in the liver as being responsible, in part, for the reduced hepatic and plasma cholesteryl esters in treated animals.

Animals↗
PubMed1994

Inhibition of PDGF receptor binding and PDGF-stimulated biological activity in vitro and of intimal lesion formation in vivo by 2-bromomethyl-5-chlorobenzene sulfonylphthalimide.

The proliferation of vascular smooth muscle cells (SMCs) is a key event in the development of atherosclerotic lesions and in the restenosis of arteries after angioplasty. Polypeptide growth factors are potent SMC mitogens in vitro and are believed to be involved in SMC proliferation in vivo. Strong data exist linking platelet-derived growth factor (PDGF) activity to human atherosclerosis. However, no low-molecular-weight antagonists of this growth factor have been discovered. We identified a compound, SCH 13929 (2-bromomethyl-5-chlorobenzene sulfonylphthalimide), which inhibits binding of 125I-PDGF BB to cell surface receptors with an IC50 of 0.13 mumol/L. This compound has a lesser effect on the binding of 125I-epidermal growth factor (EGF), 125I-basic fibroblast growth factor (bFGF), or 125I-endothelin to specific cell surface receptors. Exposure of cultured SMCs to SCH 13929 inhibits PDGF BB- and PDGF AA-stimulated DNA synthesis but not EGF- or bFGF-stimulated DNA synthesis. PDGF BB-stimulated SMC division is also inhibited by exposure to SCH 13929. Chemotaxis assays indicate that SCH 13929 inhibits PDGF-stimulated directional migration and suggest that the compound interacts with PDGF rather than with the receptor. Oral administration of SCH 13929 (100 mg/kg per day) to Sprague-Dawley rats or spontaneously hypertensive rats results in significant inhibition of lesion formation in the balloon catheter-deendothelialized carotid artery. These results suggest that SCH 13929 may be a useful tool for understanding the role of PDGF in intimal lesion formation.

3T3 Cells↗
PubMed1993

NG-nitro-L-arginine methyl ester does not affect balloon catheter-induced intimal hyperplasia in rats.

The L-arginine derived NO-cGMP pathway's role in the response of the arterial wall to balloon catheter injury was examined. Rats were given the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10 mg/kg po twice daily) or vehicle for 6 days before and 2 weeks after balloon catheter injury. NG-nitro-L-arginine methyl ester treatment increased blood pressure and inhibited acetylcholine responses in aortic rings but did not alter the lesions produced by balloon injury. Our results suggest that the L-arginine derived NO-cGMP pathway does not play a significant role in the response of the artery wall to balloon injury in the rat.

Acetylcholine↗