Mary Demarest | University of Phoenix (original) (raw)

Papers by Mary Demarest

Current Topics in Medicinal Chemistry, 2005

This review describes the role of nuclear receptors in the regulation of genes involved in choles... more This review describes the role of nuclear receptors in the regulation of genes involved in cholesterol transport and synthetic modulators of these receptors. Increasing the efflux of cholesterol from peripheral cells, such as lipid-laden macrophages, through a process called reverse cholesterol transport (RCT) requires HDL. Increasing the circulating levels of HDL, as well as the efficiency of the RCT process, could result in a reduction in the development of coronary artery disease and atherosclerosis. Nuclear receptors of the RXR heterodimer family have recently been shown to regulate key genes involved in HDL metabolism and reverse cholesterol transport. These include the PPARs (peroxisome proliferator activated receptors), the LXR (liver X receptor) and the farnesoid X receptor (FXR). The synthesis of specific and potent ligands for these receptors has aided in ascertaining the physiological role of these receptors as lipid sensors and the potential therapeutic utility of modulators of these receptors in dyslipidemias and cardiovascular disease.

Cheminform, 2004

For Abstract see ChemInform Abstract in Full Text.

Metabolism-clinical and Experimental, 2005

Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hyp... more Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hypothalamus-pituitary-adrenal axis could be a novel pharmaceutical approach to treat type 2 diabetes. In the present study, we applied an antisense oligonucleotide (ASO) against GCCR (ASO-GCCR) to reduce the expression of liver GCCR and examined its impact on the diabetic syndrome in ob/ob and db/db mice. A 3-week treatment regimen of ASO-GCCR (25 mg/kg IP, twice per week) markedly reduced liver GCCR messenger RNA and protein expression with no alteration of GCCR messenger RNA expression in the hypothalamus, pituitary, or adrenal gland. The ASO-GCCR treatment lowered blood glucose levels by 45% and 23% in ob/ob and db/db mice, respectively, compared with those observed in the control group. The ASO-GCCR-treated mice also showed significant enhancement of insulin-mediated inhibition of hepatic glucose production during a euglycemic-hyperinsulinemic clamp as well as marked reduction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity compared with control mice. The ASO-GCCR treatment did not change peripheral insulin sensitivity during the clamp. The ob/ob mice treated with ASO-GCCR had no significant difference in the plasma corticosterone and corticotropin levels compared with control mice. Lean mice receiving a similar treatment regimen of ASO-GCCR exhibited no change in blood glucose levels, oral glucose tolerance tests, or insulin tolerance tests. Our results demonstrate that selective inhibition of GCCR expression in the liver by the ASO-GCCR treatment reduced hepatic glucose production and improved blood glucose control under diabetic conditions. D

For the first time we report extremely thin SOI (ETSOI) CMOS with 22 nm gate length (LG) and sub-... more For the first time we report extremely thin SOI (ETSOI) CMOS with 22 nm gate length (LG) and sub-100 nm contacted gate pitch for system-on-chip (SoC) applications. Multi-Vt transistors are demonstrated with competitive drive currents (NFET/PFET) of 1150/1050 μA/μm at Ioff = 100 nA/μm for high performance (HP) and 920/880 μA/μm at Ioff = 1 nA/μm for low power (LP), respectively, at VDD = 1 V. High density 6-T SRAM cells down to 0.08 μm2 are demonstrated. Compared with a 28nm bulk LP technology, the high drive currents of ETSOI transistors coupled with large capacitance reduction by aggressive LG scaling result in 25% improvement in ETSOI ring oscillator (RO) speed. Auxiliary ETSOI devices including epitaxy resistors with high precision and gated diodes with near ideal characteristics are fabricated to complete device menu for early ETSOI SoC design.

Bioorganic & Medicinal Chemistry, 2008

N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradat... more N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid agonists of peroxisome proliferator-activated receptor-α, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The βlactone derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)-biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated inflammatory cells, and reduce tissue reactions to pro-inflammatory stimuli. Recently, our group disclosed ARN077 (4), a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia. In the present study, we investigated the structure−activity relationship (SAR) of threonine-derived β-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of β-lactone carbamate derivatives for NAAA and the identification of (4-phenylphenyl)-methyl-N-[(2S,3R)-2-methyl-4oxo-oxetan-3-yl]carbamate (14q) as the first single-digit nanomolar inhibitor of intracellular NAAA activity (IC 50 = 7 nM on both rat NAAA and human NAAA).

Bioorganic & Medicinal Chemistry Letters, 2007

A series of aminoindane derivatives were synthesized and shown to be potent PPARa agonists. The c... more A series of aminoindane derivatives were synthesized and shown to be potent PPARa agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARa activation and PPARa mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.

Metabolism-clinical and Experimental, 2008

Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor family o... more Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARα agonist that activated both human and rat PPARα receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid β-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARα-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARα transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARα agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.

Bioorganic & Medicinal Chemistry Letters, 2004

A novel series of spirobenzazepines was synthesized and evaluated for V 1a and V 2 receptor antag... more A novel series of spirobenzazepines was synthesized and evaluated for V 1a and V 2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V 1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V 1a /V 2 receptor antagonists.

Bioorganic & Medicinal Chemistry, 2004

Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the... more Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the first example of natural products possessing an 1,2,4-oxadiazole ring system and show various bioactivities. However, the structure-activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential neuroprotective agents, a series of phidianidine-based derivatives have been synthesized and evaluated for neuroprotective effects against amyloid-β25-35 (Aβ25-35)-, hydrogenperoxide (H2O2)-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro neuroprotective effects in the above three screening models. The preliminary SAR study indicated that substituent groups introduced to the benzene ring play a crucial role in their bioactivity. In particular, the linear alkoxy group at 4-position favors the neuroprotective activity, while a bulky group could lead the activity decrease or loss. These findings could provide an alternative strategy for the development of novel indole-based 1,2,4-oxadiazole derivatives for the treatment of Alzheimer's disease.

Clinical Neuropsychologist, 1996

Current Topics in Medicinal Chemistry, 2005

This review describes the role of nuclear receptors in the regulation of genes involved in choles... more This review describes the role of nuclear receptors in the regulation of genes involved in cholesterol transport and synthetic modulators of these receptors. Increasing the efflux of cholesterol from peripheral cells, such as lipid-laden macrophages, through a process called reverse cholesterol transport (RCT) requires HDL. Increasing the circulating levels of HDL, as well as the efficiency of the RCT process, could result in a reduction in the development of coronary artery disease and atherosclerosis. Nuclear receptors of the RXR heterodimer family have recently been shown to regulate key genes involved in HDL metabolism and reverse cholesterol transport. These include the PPARs (peroxisome proliferator activated receptors), the LXR (liver X receptor) and the farnesoid X receptor (FXR). The synthesis of specific and potent ligands for these receptors has aided in ascertaining the physiological role of these receptors as lipid sensors and the potential therapeutic utility of modulators of these receptors in dyslipidemias and cardiovascular disease.

Cheminform, 2004

For Abstract see ChemInform Abstract in Full Text.

Metabolism-clinical and Experimental, 2005

Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hyp... more Specific blockade of glucocorticoid receptor (GCCR) action in the liver without affecting the hypothalamus-pituitary-adrenal axis could be a novel pharmaceutical approach to treat type 2 diabetes. In the present study, we applied an antisense oligonucleotide (ASO) against GCCR (ASO-GCCR) to reduce the expression of liver GCCR and examined its impact on the diabetic syndrome in ob/ob and db/db mice. A 3-week treatment regimen of ASO-GCCR (25 mg/kg IP, twice per week) markedly reduced liver GCCR messenger RNA and protein expression with no alteration of GCCR messenger RNA expression in the hypothalamus, pituitary, or adrenal gland. The ASO-GCCR treatment lowered blood glucose levels by 45% and 23% in ob/ob and db/db mice, respectively, compared with those observed in the control group. The ASO-GCCR-treated mice also showed significant enhancement of insulin-mediated inhibition of hepatic glucose production during a euglycemic-hyperinsulinemic clamp as well as marked reduction of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity compared with control mice. The ASO-GCCR treatment did not change peripheral insulin sensitivity during the clamp. The ob/ob mice treated with ASO-GCCR had no significant difference in the plasma corticosterone and corticotropin levels compared with control mice. Lean mice receiving a similar treatment regimen of ASO-GCCR exhibited no change in blood glucose levels, oral glucose tolerance tests, or insulin tolerance tests. Our results demonstrate that selective inhibition of GCCR expression in the liver by the ASO-GCCR treatment reduced hepatic glucose production and improved blood glucose control under diabetic conditions. D

For the first time we report extremely thin SOI (ETSOI) CMOS with 22 nm gate length (LG) and sub-... more For the first time we report extremely thin SOI (ETSOI) CMOS with 22 nm gate length (LG) and sub-100 nm contacted gate pitch for system-on-chip (SoC) applications. Multi-Vt transistors are demonstrated with competitive drive currents (NFET/PFET) of 1150/1050 μA/μm at Ioff = 100 nA/μm for high performance (HP) and 920/880 μA/μm at Ioff = 1 nA/μm for low power (LP), respectively, at VDD = 1 V. High density 6-T SRAM cells down to 0.08 μm2 are demonstrated. Compared with a 28nm bulk LP technology, the high drive currents of ETSOI transistors coupled with large capacitance reduction by aggressive LG scaling result in 25% improvement in ETSOI ring oscillator (RO) speed. Auxiliary ETSOI devices including epitaxy resistors with high precision and gated diodes with near ideal characteristics are fabricated to complete device menu for early ETSOI SoC design.

Bioorganic & Medicinal Chemistry, 2008

N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradat... more N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid agonists of peroxisome proliferator-activated receptor-α, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). The βlactone derivatives (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide (2) and (S)-N-(2-oxo-3-oxetanyl)-biphenyl-4-carboxamide (3) inhibit NAAA, prevent FAE hydrolysis in activated inflammatory cells, and reduce tissue reactions to pro-inflammatory stimuli. Recently, our group disclosed ARN077 (4), a potent NAAA inhibitor that is active in vivo by topical administration in rodent models of hyperalgesia and allodynia. In the present study, we investigated the structure−activity relationship (SAR) of threonine-derived β-lactone analogues of compound 4. The main results of this work were an enhancement of the inhibitory potency of β-lactone carbamate derivatives for NAAA and the identification of (4-phenylphenyl)-methyl-N-[(2S,3R)-2-methyl-4oxo-oxetan-3-yl]carbamate (14q) as the first single-digit nanomolar inhibitor of intracellular NAAA activity (IC 50 = 7 nM on both rat NAAA and human NAAA).

Bioorganic & Medicinal Chemistry Letters, 2007

A series of aminoindane derivatives were synthesized and shown to be potent PPARa agonists. The c... more A series of aminoindane derivatives were synthesized and shown to be potent PPARa agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARa activation and PPARa mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.

Metabolism-clinical and Experimental, 2008

Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor family o... more Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARα agonist that activated both human and rat PPARα receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid β-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARα-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARα transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARα agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.

Bioorganic & Medicinal Chemistry Letters, 2004

A novel series of spirobenzazepines was synthesized and evaluated for V 1a and V 2 receptor antag... more A novel series of spirobenzazepines was synthesized and evaluated for V 1a and V 2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V 1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V 1a /V 2 receptor antagonists.

Bioorganic & Medicinal Chemistry, 2004

Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the... more Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the first example of natural products possessing an 1,2,4-oxadiazole ring system and show various bioactivities. However, the structure-activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential neuroprotective agents, a series of phidianidine-based derivatives have been synthesized and evaluated for neuroprotective effects against amyloid-β25-35 (Aβ25-35)-, hydrogenperoxide (H2O2)-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro neuroprotective effects in the above three screening models. The preliminary SAR study indicated that substituent groups introduced to the benzene ring play a crucial role in their bioactivity. In particular, the linear alkoxy group at 4-position favors the neuroprotective activity, while a bulky group could lead the activity decrease or loss. These findings could provide an alternative strategy for the development of novel indole-based 1,2,4-oxadiazole derivatives for the treatment of Alzheimer's disease.

Clinical Neuropsychologist, 1996