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Harry R Davis - One of the best experts on this subject based on the ideXlab platform.
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niemann pick c1 like 1 npc1l1 an intestinal sterol transporter
Biochimica et Biophysica Acta, 2009Co-Authors: Harry R Davis, Scott W AltmannAbstract:Abstract Niemann–Pick C1 Like 1 (NPC1L1) has been identified and characterized as an essential protein in the intestinal Cholesterol Absorption process. NPC1L1 localizes to the brush border membrane of absorptive enterocytes in the small intestine. Intestinal expression of NPC1L1 is down regulated by diets containing high levels of Cholesterol. While otherwise phenotypically normal, Npc1l1 null mice exhibit a significant reduction in the intestinal uptake and Absorption of Cholesterol and phytosterols. Characterization of the NPC1L1 pathway revealed that Cholesterol Absorption Inhibitor ezetimibe specifically binds to an extracellular loop of NPC1L1 and inhibits its sterol transport function. Npc1l1 null mice are resistant to diet-induced hyperCholesterolemia, and when crossed with apo E null mice, are completely resistant to the development of atherosclerosis. Intestinal gene expression studies in Npc1l1 null mice indicated that no exogenous Cholesterol was entering enterocytes lacking NPC1L1, which resulted in an upregulation of intestinal and hepatic LDL receptor and Cholesterol biosynthetic gene expression. Polymorphisms in the human NPC1L1 gene have been found to influence Cholesterol Absorption and plasma low density lipoprotein levels. Therefore, NPC1L1 is a critical intestinal sterol uptake transporter which influences whole body Cholesterol homeostasis.
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Niemann–Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter
Biochimica et Biophysica Acta, 2009Co-Authors: Harry R Davis, Scott W AltmannAbstract:Abstract Niemann–Pick C1 Like 1 (NPC1L1) has been identified and characterized as an essential protein in the intestinal Cholesterol Absorption process. NPC1L1 localizes to the brush border membrane of absorptive enterocytes in the small intestine. Intestinal expression of NPC1L1 is down regulated by diets containing high levels of Cholesterol. While otherwise phenotypically normal, Npc1l1 null mice exhibit a significant reduction in the intestinal uptake and Absorption of Cholesterol and phytosterols. Characterization of the NPC1L1 pathway revealed that Cholesterol Absorption Inhibitor ezetimibe specifically binds to an extracellular loop of NPC1L1 and inhibits its sterol transport function. Npc1l1 null mice are resistant to diet-induced hyperCholesterolemia, and when crossed with apo E null mice, are completely resistant to the development of atherosclerosis. Intestinal gene expression studies in Npc1l1 null mice indicated that no exogenous Cholesterol was entering enterocytes lacking NPC1L1, which resulted in an upregulation of intestinal and hepatic LDL receptor and Cholesterol biosynthetic gene expression. Polymorphisms in the human NPC1L1 gene have been found to influence Cholesterol Absorption and plasma low density lipoprotein levels. Therefore, NPC1L1 is a critical intestinal sterol uptake transporter which influences whole body Cholesterol homeostasis.
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niemann pick c1 like 1 npc1l1 is the intestinal phytosterol and Cholesterol transporter and a key modulator of whole body Cholesterol homeostasis
Journal of Biological Chemistry, 2004Co-Authors: Harry R Davis, Lizbeth M Hoos, Glen Tetzloff, Sai Prasad N Iyer, Maureen Maguire, Erik G. Lund, Patricia A Detmers, Michael P Graziano, Scott W AltmannAbstract:Abstract Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal Cholesterol Absorption. The uptake of intestinal phytosterols and Cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body Cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of Cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hyperCholesterolemia, with plasma lipoprotein and hepatic Cholesterol profiles similar to those of wild type mice treated with the Cholesterol Absorption Inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal Cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both Cholesterol and phytosterols and plays a major role in Cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hyperCholesterolemia and sitosterolemia.
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Ezetimibe: first in a new class of Cholesterol Absorption Inhibitors
International Congress Series, 2004Co-Authors: Harry R DavisAbstract:Ezetimibe is a selective Cholesterol Absorption Inhibitor, which potently inhibits the Absorption of biliary and dietary Cholesterol from the small intestine without affecting the Absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and Absorption of Cholesterol, which keeps the Cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it prevents Cholesterol Absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug–drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit Cholesterol Absorption by an average of 54% in hyperCholesterolemic individuals (p
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Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of Cholesterol Absorption Inhibitors.
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Duane A. Burnett, Scott W Altmann, Harry R Davis, Mary Ann Caplen, Margaret E Browne, Hongrong Zhau, John W. CladerAbstract:Fluorescent analogues of the Cholesterol Absorption Inhibitor (CAI), Sch 58235, have been designed and synthesized as single enantiomers. Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA).
Margaret Van Heek - One of the best experts on this subject based on the ideXlab platform.
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ezetimibe a potent Cholesterol Absorption Inhibitor normalizes combined dyslipidemia in obese hyperinsulinemic hamsters
Diabetes, 2001Co-Authors: Margaret Van Heek, Glen Tetzloff, Theodore M Austin, Constance Farley, John Cook, Harry R DavisAbstract:Ezetimibe potently and selectively inhibits Cholesterol Absorption in the intestine, thereby reducing plasma Cholesterol in preclinical models of hyperCholesterolemia. Clinical trials have demonstrated that ezetimibe lowers LDL Cholesterol and raises HDL Cholesterol in humans. The effect of ezetimibe on other dyslipidemias, particularly hypertriglyceridemia, is not yet known. In the present studies, we assessed the effect of ezetimibe on combined hyperCholesterolemia and hypertriglyceridemia in obese hyperinsulinemic hamsters. Hamsters were fed chow, chow with Cholesterol (0.12%), or the same Cholesterol diet containing different dietary triglycerides (15%) in the absence or presence of 1 mg/kg ezetimibe (in diet) for up to 84 days. Body weight, serum insulin, leptin, glucose, Cholesterol, and triglyceride levels were analyzed. Cholesterol and triglyceride levels were also determined in VLDL+IDL, LDL, and HDL. Hamsters maintained on high-fat diets became obese, hyperinsulinemic, hyperleptinemic, hyperCholesterolemic, and hypertriglyceridemic. Ezetimibe did not affect body weight, insulin, or leptin, but ablated the combined hyperCholesterolemia and hypertriglyceridemia induced by high-fat diets. Ezetimibe normalized VLDL+IDL Cholesterol and triglyceride and significantly decreased LDL Cholesterol to below chow-fed levels. The ratio of HDL to LDL Cholesterol increased significantly with the addition of ezetimibe. Ezetimibe completely eliminated the accumulation of cholesteryl ester and free Cholesterol in liver that was induced under the various dietary conditions in the absence of drug. In conclusion, ezetimibe is very effective in correcting the combined dyslipidemia in diet-induced obese hyperinsulinemic hamsters and may be an effective therapy for ameliorating combined dyslipidemia in obese insulin-resistant and/or type 2 diabetic humans.
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The Cholesterol Absorption Inhibitor, ezetimibe, decreases diet-induced hyperCholesterolemia in monkeys.
European Journal of Pharmacology, 2001Co-Authors: Margaret Van Heek, Douglas S Compton, Harry R DavisAbstract:Abstract Ezetimibe (1-(4-fluorophenyl)-(3 R )-[3-(4-fluorophenyl)-(3 S )-hydroxypropyl]-(4 S )-(4-hydroxyphenyl)-2-azetidinone) potently and selectively inhibits the intestinal Absorption of Cholesterol, thereby reducing plasma Cholesterol in preclinical models of hyperCholesterolemia. In rhesus monkeys fed a diet containing 375 mg/day of Cholesterol, 0.1 mg/kg of ezetimibe completely prevented the doubling of plasma Cholesterol normally induced under these dietary conditions (ED 50 =0.0005 mg/kg). Low-density lipoprotein Cholesterol (LDL) was dose-dependently reduced, while high-density lipoprotein Cholesterol (HDL) and plasma triglyceride were unchanged. A single dose of an ezetimibe analog administered to cynomolgus monkeys fed a single Cholesterol-containing meal caused a significant reduction (−69%) of Cholesterol in chylomicrons during the postprandial phase without affecting triglyceride content. In rhesus monkeys, apolipoprotein (apo) B 48 concentrations in chylomicrons did not differ between control and the ezetimibe analog, but apo B 100 was significantly reduced in LDL (−41%). These data indicate that these Cholesterol Absorption Inhibitors reduce Cholesterol content in chylomicrons, which indirectly leads to a decrease in LDL Cholesterol and particle number.
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comparison of the activity and disposition of the novel Cholesterol Absorption Inhibitor sch58235 and its glucuronide sch60663
British Journal of Pharmacology, 2000Co-Authors: Margaret Van Heek, Lizbeth M Hoos, Douglas S Compton, Kevin B. Alton, Edmund J Sybertz, Constance Farley, Harry R DavisAbstract:Previous studies described the metabolism-based discovery of a potent, selective Inhibitor of intestinal Absorption of Cholesterol, SCH58235 (Ezetimibe). Here we demonstrate that the phenolic glucuronide (SCH60663) of SCH58235, was more potent at inhibiting Cholesterol Absorption in rats than SCH58235, when administered by the intraduodenal route. To understand the increased potency of the glucuronide, the metabolism and distribution of SCH58235 and SCH60663 were studied in bile duct-cannulated rats. One minute after intraduodenal delivery of SCH58235, significant levels of compound were detected in portal plasma; >95% was glucuronidated, indicating that the intestine was metabolizing SCH58235 to its glucuronide. When intraduodenally delivered as SCH58235, the compound was glucuronidated, moved through the intestinal wall, into portal plasma, through the liver, and into bile. However, when delivered as SCH60663, >95% of the compound remained in the intestinal lumen and wall, which may explain its increased potency. Significant inhibition of Cholesterol Absorption and glucuronidation of SCH58235 occurred when SCH58235 was intravenously injected into bile duct-cannulated rats. Autoradiographic analysis demonstrated that drug related material was located throughout the intestinal villi, but concentrated in the villus tip. These data indicate that (a) SCH58235 is rapidly metabolized in the intestine to its glucuronide; (b) once glucuronidated, the dose is excreted in the bile, thereby delivering drug related material back to the site of action and (c) the glucuronide is more potent than the parent possibly because it localizes to the intestine. Taken together, these data may explain the potency of SCH58235 in the rat (ID(50) = 0.0015 mg kg(-1)) and rhesus monkey (ID(50) = 0.0005 mg kg(-1)).
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sch 57939 synthesis and pharmacological properties of a potent metabolically stable Cholesterol Absorption Inhibitor
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Michael P. Kirkup, Sundeep Dugar, Razia Rizvi, John W. Clader, Stuart W. Mccombie, Bandarpalle B. Shankar, Sue-ing Lin, Nathan Yumibe, Keith Huie, Margaret Van HeekAbstract:Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a Cholesterol Absorption Inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.
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metabolism and structure activity data based drug design discovery of sch 53079 an analog of the potent Cholesterol Absorption Inhibitor sch 48461
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Sundeep Dugar, John W. Clader, Nathan Yumibe, Keith Huie, Margaret Van Heek, Monica Vizziano, Douglas S Compton, Harry R DavisAbstract:Abstract Based on the metabolism of the potent Cholesterol Absorption Inhibitor (−) SCH48461 and structure activity relationship information, we designed and evaluated (−)SCH 53079. This compound was found to be equipotent to (−)SCH 48461 in both the Cholesterol-fed hamster and rhesus monkey assays. Importantly, (−)SCH 53079 was metabolically more stable than (−)SCH 48461 and as desired had very low plasma levels and did not cause hepatic enzyme induction.
Sundeep Dugar - One of the best experts on this subject based on the ideXlab platform.
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sch 57939 synthesis and pharmacological properties of a potent metabolically stable Cholesterol Absorption Inhibitor
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Michael P. Kirkup, Sundeep Dugar, Razia Rizvi, John W. Clader, Stuart W. Mccombie, Bandarpalle B. Shankar, Sue-ing Lin, Nathan Yumibe, Keith Huie, Margaret Van HeekAbstract:Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a Cholesterol Absorption Inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.
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metabolism and structure activity data based drug design discovery of sch 53079 an analog of the potent Cholesterol Absorption Inhibitor sch 48461
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Sundeep Dugar, John W. Clader, Nathan Yumibe, Keith Huie, Margaret Van Heek, Monica Vizziano, Douglas S Compton, Harry R DavisAbstract:Abstract Based on the metabolism of the potent Cholesterol Absorption Inhibitor (−) SCH48461 and structure activity relationship information, we designed and evaluated (−)SCH 53079. This compound was found to be equipotent to (−)SCH 48461 in both the Cholesterol-fed hamster and rhesus monkey assays. Importantly, (−)SCH 53079 was metabolically more stable than (−)SCH 48461 and as desired had very low plasma levels and did not cause hepatic enzyme induction.
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(−)-SCH 57939: synthesis and pharmacological properties of a potent, metabolically stable Cholesterol Absorption Inhibitor
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Michael P. Kirkup, Sundeep Dugar, Razia Rizvi, John W. Clader, Stuart W. Mccombie, Bandarpalle B. Shankar, Sue-ing Lin, Nathan Yumibe, Keith Huie, Margaret Van HeekAbstract:Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a Cholesterol Absorption Inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.
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Metabolism and structure activity data based drug design: discovery of (−) SCH 53079 an analog of the potent Cholesterol Absorption Inhibitor (−) SCH 48461
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Sundeep Dugar, John W. Clader, Nathan Yumibe, Keith Huie, Margaret Van Heek, Monica Vizziano, Douglas S Compton, Harry R DavisAbstract:Abstract Based on the metabolism of the potent Cholesterol Absorption Inhibitor (−) SCH48461 and structure activity relationship information, we designed and evaluated (−)SCH 53079. This compound was found to be equipotent to (−)SCH 48461 in both the Cholesterol-fed hamster and rhesus monkey assays. Importantly, (−)SCH 53079 was metabolically more stable than (−)SCH 48461 and as desired had very low plasma levels and did not cause hepatic enzyme induction.
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Gamma-lactams and related compounds as Cholesterol Absorption Inhibitors: homologs of the beta-lactam Cholesterol Absorption Inhibitor SCH 484611
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: Sundeep Dugar, Razia Rizvi, M.e. Snow, John W. Clader, Michael P. Kirkup, Harry R Davis, Stuart W. MccombieAbstract:Abstract Our search for potent Cholesterol Absorption Inhibitors led to the discovery of the β-lactam SCH 48461. Structure activity relationship studies prompted us to this study of γ-lactams, ring homologs of β-lactam SCH 48461, to determine their potential as Cholesterol Absorption Inhibitors. The results indicate that the γ-lactams have moderate Cholesterol Absorption Inhibitory properties.
Nathan Yumibe - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: M Van Heek, Nathan Yumibe, Douglas S Compton, Kevin B. Alton, Robbie L Mcleod, Edmund J Sybertz, Harry R DavisAbstract: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.
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sch 57939 synthesis and pharmacological properties of a potent metabolically stable Cholesterol Absorption Inhibitor
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Michael P. Kirkup, Sundeep Dugar, Razia Rizvi, John W. Clader, Stuart W. Mccombie, Bandarpalle B. Shankar, Sue-ing Lin, Nathan Yumibe, Keith Huie, Margaret Van HeekAbstract:Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a Cholesterol Absorption Inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.
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metabolism and structure activity data based drug design discovery of sch 53079 an analog of the potent Cholesterol Absorption Inhibitor sch 48461
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Sundeep Dugar, John W. Clader, Nathan Yumibe, Keith Huie, Margaret Van Heek, Monica Vizziano, Douglas S Compton, Harry R DavisAbstract:Abstract Based on the metabolism of the potent Cholesterol Absorption Inhibitor (−) SCH48461 and structure activity relationship information, we designed and evaluated (−)SCH 53079. This compound was found to be equipotent to (−)SCH 48461 in both the Cholesterol-fed hamster and rhesus monkey assays. Importantly, (−)SCH 53079 was metabolically more stable than (−)SCH 48461 and as desired had very low plasma levels and did not cause hepatic enzyme induction.
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(−)-SCH 57939: synthesis and pharmacological properties of a potent, metabolically stable Cholesterol Absorption Inhibitor
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Michael P. Kirkup, Sundeep Dugar, Razia Rizvi, John W. Clader, Stuart W. Mccombie, Bandarpalle B. Shankar, Sue-ing Lin, Nathan Yumibe, Keith Huie, Margaret Van HeekAbstract:Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a Cholesterol Absorption Inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.
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Metabolism and structure activity data based drug design: discovery of (−) SCH 53079 an analog of the potent Cholesterol Absorption Inhibitor (−) SCH 48461
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Sundeep Dugar, John W. Clader, Nathan Yumibe, Keith Huie, Margaret Van Heek, Monica Vizziano, Douglas S Compton, Harry R DavisAbstract:Abstract Based on the metabolism of the potent Cholesterol Absorption Inhibitor (−) SCH48461 and structure activity relationship information, we designed and evaluated (−)SCH 53079. This compound was found to be equipotent to (−)SCH 48461 in both the Cholesterol-fed hamster and rhesus monkey assays. Importantly, (−)SCH 53079 was metabolically more stable than (−)SCH 48461 and as desired had very low plasma levels and did not cause hepatic enzyme induction.
John W. Clader - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of Cholesterol Absorption Inhibitors.
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Duane A. Burnett, Scott W Altmann, Harry R Davis, Mary Ann Caplen, Margaret E Browne, Hongrong Zhau, John W. CladerAbstract:Fluorescent analogues of the Cholesterol Absorption Inhibitor (CAI), Sch 58235, have been designed and synthesized as single enantiomers. Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA).
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sch 57939 synthesis and pharmacological properties of a potent metabolically stable Cholesterol Absorption Inhibitor
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Michael P. Kirkup, Sundeep Dugar, Razia Rizvi, John W. Clader, Stuart W. Mccombie, Bandarpalle B. Shankar, Sue-ing Lin, Nathan Yumibe, Keith Huie, Margaret Van HeekAbstract:Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a Cholesterol Absorption Inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.
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metabolism and structure activity data based drug design discovery of sch 53079 an analog of the potent Cholesterol Absorption Inhibitor sch 48461
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Sundeep Dugar, John W. Clader, Nathan Yumibe, Keith Huie, Margaret Van Heek, Monica Vizziano, Douglas S Compton, Harry R DavisAbstract:Abstract Based on the metabolism of the potent Cholesterol Absorption Inhibitor (−) SCH48461 and structure activity relationship information, we designed and evaluated (−)SCH 53079. This compound was found to be equipotent to (−)SCH 48461 in both the Cholesterol-fed hamster and rhesus monkey assays. Importantly, (−)SCH 53079 was metabolically more stable than (−)SCH 48461 and as desired had very low plasma levels and did not cause hepatic enzyme induction.
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(−)-SCH 57939: synthesis and pharmacological properties of a potent, metabolically stable Cholesterol Absorption Inhibitor
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Michael P. Kirkup, Sundeep Dugar, Razia Rizvi, John W. Clader, Stuart W. Mccombie, Bandarpalle B. Shankar, Sue-ing Lin, Nathan Yumibe, Keith Huie, Margaret Van HeekAbstract:Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a Cholesterol Absorption Inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.
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Metabolism and structure activity data based drug design: discovery of (−) SCH 53079 an analog of the potent Cholesterol Absorption Inhibitor (−) SCH 48461
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Sundeep Dugar, John W. Clader, Nathan Yumibe, Keith Huie, Margaret Van Heek, Monica Vizziano, Douglas S Compton, Harry R DavisAbstract:Abstract Based on the metabolism of the potent Cholesterol Absorption Inhibitor (−) SCH48461 and structure activity relationship information, we designed and evaluated (−)SCH 53079. This compound was found to be equipotent to (−)SCH 48461 in both the Cholesterol-fed hamster and rhesus monkey assays. Importantly, (−)SCH 53079 was metabolically more stable than (−)SCH 48461 and as desired had very low plasma levels and did not cause hepatic enzyme induction.