-
Zhijian Lu,
Yi-Heng Chen,
Joann B Napolitano,
Gayle Taylor,
Amjad Ali,
Milton L Hammond,
Qiaolin Deng,
Eugene Tan,
Xinchun Tong,
Suoyu S Xu, [......],
Laurence B Peterson,
Matt S Anderson,
Suzanne S Eveland, Qiu Guo,
Sheryl A Hyland,
Denise P Milot,
Ying Chen,
Carl P Sparrow,
Samuel D Wright,
Peter J Sinclair
[show abstract]
[hide abstract]
ABSTRACT: SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF(3) derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (>20mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.
Bioorganic & medicinal chemistry letters 11/2011; 22(1):199-203. · 2.65 Impact Factor
-
Cameron J Smith,
Amjad Ali,
Milton L Hammond,
Hong Li,
Zhijian Lu,
Joann Napolitano,
Gayle E Taylor,
Christopher F Thompson,
Matt S Anderson,
Ying Chen, [......],
Carl P Sparrow,
Samuel D Wright,
Anne-Marie Cumiskey,
Melanie Latham,
Laurence B Peterson,
Ray Rosa,
James V Pivnichny,
Xinchun Tong,
Suoyu S Xu,
Peter J Sinclair
[show abstract]
[hide abstract]
ABSTRACT: The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.
Journal of Medicinal Chemistry 06/2011; 54(13):4880-95. · 4.80 Impact Factor
-
Christopher F. Thompson,
Amjad Ali,
Nazia Quraishi,
Zhijian Lu,
Milton L. Hammond,
Peter J. Sinclair,
Matt S. Anderson,
Suzanne S. Eveland, Qiu Guo,
Sheryl A. Hyland,
Denise P. Milot,
Carl P. Sparrow,
Samuel D. Wright
[show abstract]
[hide abstract]
ABSTRACT: Recently, there has been a strong interest in the ability to increase levels of high density lipoprotein-cholesterol (HDL-C). This interest stems from the hypothesis that such an elevation in HDL-C will decrease the likelihood of cardiovascular disease. Inhibition of cholesteryl ester transfer protein (CETP) has been shown to elevate HDL-C levels in human subjects. This letter describes the discovery of a novel and potent (<100 nM IC50 for the inhibition of CE transfer) CETP inhibitor scaffold containing an oxazolidinone core.Keywords: Cholesteryl ester transfer protein; CETP; cardiovascular disease; high density lipoprotein; HDL; oxazolidinone
03/2011;
-
Ramzi F Sweis,
Julianne A Hunt,
Peter J Sinclair,
Ying Chen,
Suzanne S Eveland, Qiu Guo,
Sheryl A Hyland,
Denise P Milot,
Anne-Marie Cumiskey,
Melanie Latham,
Raymond Rosa,
Larry Peterson,
Carl P Sparrow,
Matt S Anderson
[show abstract]
[hide abstract]
ABSTRACT: The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.
Bioorganic & medicinal chemistry letters 02/2011; 21(9):2597-600. · 2.65 Impact Factor
-
Florida Kallashi,
Dooseop Kim,
Jennifer Kowalchick,
You Jung Park,
Julianne A Hunt,
Amjad Ali,
Cameron J Smith,
Milton L Hammond,
James V Pivnichny,
Xinchun Tong, [......], Qiu Guo,
Sheryl A Hyland,
Denise P Milot,
Anne-Marie Cumiskey,
Melanie Latham,
Laurence B Peterson,
Raymond Rosa,
Carl P Sparrow,
Samuel D Wright,
Peter J Sinclair
[show abstract]
[hide abstract]
ABSTRACT: We describe structure-activity studies leading to the discovery of 2-arylbenzoxazole 3, the first in a series to raise serum high-density lipoprotein cholesterol levels in transgenic mice. Replacement of the 4-piperidinyloxy moiety with piperazinyl provided a more synthetically tractable lead, which upon optimization resulted in compound 4, an excellent inhibitor of cholesteryl ester transfer protein function with good pharmacokinetic properties and in vivo efficacy.
Bioorganic & medicinal chemistry letters 01/2011; 21(1):558-61. · 2.65 Impact Factor
-
Ramzi F Sweis,
Julianne A Hunt,
Florida Kallashi,
Milton L Hammond,
Ying Chen,
Suzanne S Eveland, Qiu Guo,
Sheryl A Hyland,
Denise P Milot,
Anne-Marie Cumiskey,
Melanie Latham,
Raymond Rosa,
Larry Peterson,
Carl P Sparrow,
Samuel D Wright,
Matt S Anderson,
Peter J Sinclair
[show abstract]
[hide abstract]
ABSTRACT: The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Initial efforts aimed at engineering replacements for the aniline substructures in the benchmark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphenyl)benzoxazoles. Structure-activity studies at the C-7 and terminal pyridine ring allowed for the optimization of potency and HDLc-raising efficacy in this new class of inhibitors. These efforts lead to the discovery of benzoxazole 11v, which raised HDLc by 24 mg/dl in our transgenic mouse PD model.
Bioorganic & medicinal chemistry letters 11/2010; 21(6):1890-5. · 2.65 Impact Factor
-
Zhijian Lu,
Joann B Napolitano,
Ashleigh Theberge,
Amjad Ali,
Milton L Hammond,
Eugene Tan,
Xinchun Tong,
Suoyu S Xu,
Melanie J Latham,
Laurence B Peterson,
Matt S Anderson,
Suzanne S Eveland, Qiu Guo,
Sheryl A Hyland,
Denise P Milot,
Ying Chen,
Carl P Sparrow,
Samuel D Wright,
Peter J Sinclair
[show abstract]
[hide abstract]
ABSTRACT: A new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic mouse PD model.
Bioorganic & medicinal chemistry letters 10/2010; 20(24):7469-72. · 2.65 Impact Factor
-
Julianne A Hunt,
Silvia Gonzalez,
Florida Kallashi,
Milton L Hammond,
James V Pivnichny,
Xinchun Tong,
Suoyu S Xu,
Matt S Anderson,
Ying Chen,
Suzanne S Eveland, Qiu Guo,
Sheryl A Hyland,
Denise P Milot,
Carl P Sparrow,
Samuel D Wright,
Peter J Sinclair
[show abstract]
[hide abstract]
ABSTRACT: The development of a series of 2-arylbenzoxazole alpha-alkoxyamide and beta-alkoxyamine inhibitors of cholesteryl ester transfer protein (CETP) is described. Highly fluorinated alpha-alkoxyamides proved to be potent inhibitors of CETP in vitro, and the highly fluorinated 2-arylbenzoxazole beta-alkoxyamine 4 showed a desirable combination of in vitro potency (IC(50)=151 nM) and oral bioavailability in the mouse.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):1019-22. · 2.65 Impact Factor
-
Cameron J Smith,
Amjad Ali,
Liya Chen,
Milton L Hammond,
Matt S Anderson,
Ying Chen,
Suzanne S Eveland, Qiu Guo,
Sheryl A Hyland,
Denise P Milot,
Carl P Sparrow,
Samuel D Wright,
Peter J Sinclair
[show abstract]
[hide abstract]
ABSTRACT: A series of 2-arylbenzoxazole inhibitors of the cholesterol ester transfer protein (CETP) is described. Structure-activity studies focused on variation of the substitution of the benzoxazole moiety. Substitution at the 5- and 7-positions of the benzoxazole moiety was found to be beneficial for CETP inhibition. Compound 47 was found to be the most potent inhibitor in this series and inhibited CETP with an IC(50) of 28nM.
Bioorganic & medicinal chemistry letters 10/2009; 20(1):346-9. · 2.65 Impact Factor
-
Suzanne S Eveland,
Denise P Milot, Qiu Guo,
Ying Chen,
Sheryl A Hyland,
Laurence B Peterson,
Sylvie Jezequel-Sur,
Gregory T O'Donnell,
Paul D Zuck,
Marc Ferrer,
Berta Strulovici,
John A Wagner,
Wesley K Tanaka,
Deborah A Hilliard,
Omar Laterza,
Samuel D Wright,
Carl P Sparrow,
Matt S Anderson
[show abstract]
[hide abstract]
ABSTRACT: Cholesteryl ester transfer protein (CETP) is a serum component responsible for both cholesteryl ester and triglyceride trafficking between high-density lipoprotein (HDL) and the apolipoprotein B (apoB)-containing very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Several fluorescence-based assays that monitor these transfers have been reported, but to date such assays have suffered from a low signal/background (S/B) ratio and have been described for use only in relatively purified in vitro systems. We have modified the more advanced of these assays to incorporate a noninterfering, nondiffusable fluorescence quencher into previously described cosonicate particles, often referred to as microemulsions. This simple improvement resulted in particles that had an average threefold enhanced S/B window over particles without quenchers but that continued to show the essential properties of a catalytic assay, including catalysis to a single endpoint, excellent linearity with protein and particle concentration, and an appropriate sensitivity to inhibition. This reduced assay noise allowed the subsequent development of protocols for the direct measure of cholesteryl ester (CE) transfer activity resident in human and animal serum as well as the development of 384- and 3456-well screening protocols with good precision and accuracy. Thus, by expanding the dynamic response window of the assay, we have created an assay generalizable to many settings.
Analytical Biochemistry 10/2007; 368(2):239-49. · 3.00 Impact Factor
-
Erik G Lund,
Laurence B Peterson,
Alan D Adams,
My-Hanh N Lam,
Charlotte A Burton,
Jayne Chin, Qiu Guo,
Shaei Huang,
Melanie Latham,
Jacqueline C Lopez,
John G Menke,
Denise P Milot,
Lyndon J Mitnaul,
Sandra E Rex-Rabe,
Raymond L Rosa,
Jenny Y Tian,
Samuel D Wright,
Carl P Sparrow
[show abstract]
[hide abstract]
ABSTRACT: Liver X receptor (LXR) alpha and LXRbeta are closely related nuclear receptors that respond to elevated levels of intracellular cholesterol by enhancing transcription of genes that control cholesterol efflux and fatty acid biosynthesis. The consequences of inactivation of either LXR isoform have been thoroughly studied, as have the effects of simultaneous activation of both LXRalpha and LXRbeta by synthetic compounds. We here describe the effects of selective activation of LXRalpha or LXRbeta on lipid metabolism. This was accomplished by treating mice genetically deficient in either LXRalpha or LXRbeta with an agonist with equal potency for both isoforms (Compound B) or a synthetic agonist selective for LXRalpha (Compound A). We also determined the effect of these agonists on gene expression and cholesterol efflux in peritoneal macrophages derived from wild-type and knockout mice. Both compounds raised HDL-cholesterol and increased liver triglycerides in wild-type mice; in contrast, in mice deficient in LXRalpha, Compound B increased HDL-cholesterol but did not cause hepatic steatosis. Compound B induced ATP-binding cassette transporter (ABC) A1 expression and stimulated cholesterol efflux in macrophages from both LXRalpha and LXRbeta-deficient mice. Our data lend further experimental support to the hypothesis that LXRbeta-selective agonists may raise HDL-cholesterol and stimulate macrophage cholesterol efflux without causing liver triglyceride accumulation.
Biochemical Pharmacology 03/2006; 71(4):453-63. · 4.70 Impact Factor
-
Qiu Guo,
Soumya P Sahoo,
Pei-Ran Wang,
Denise P Milot,
Marc C Ippolito,
Margaret S Wu,
Joanne Baffic,
Chhabi Biswas,
Melba Hernandez,
My-Hanh Lam, [......],
Karen L MacNaul,
Gaochao Zhou,
Ranjit Desai,
James V Heck,
Thomas W Doebber,
Joel P Berger,
David E Moller,
Carl P Sparrow,
Yu-Sheng Chao,
Samuel D Wright
[show abstract]
[hide abstract]
ABSTRACT: Patients with type 2 diabetes mellitus exhibit hyperglycemia and dyslipidemia as well as a markedly increased incidence of atherosclerotic cardiovascular disease. Here we report the characterization of a novel arylthiazolidinedione capable of lowering both glucose and lipid levels in animal models. This compound, designated TZD18, is a potent agonist with dual human peroxisome proliferator-activated receptor (PPAR)-alpha/gamma activities. In keeping with its PPARgamma activity, TZD18 caused complete normalization of the elevated glucose in db/db mice and Zucker diabetic fatty rats. TZD18 lowered both cholesterol and triglycerides in hamsters and dogs. TZD18 inhibited cholesterol biosynthesis at steps before mevalonate and reduced hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Moreover, TZD18 significantly suppressed gene expression of fatty acid synthesis and induced expression of genes for fatty acid degradation and triglyceride clearance. Studies on 17 additional PPARalpha or PPARalpha/gamma agonists showed that lipid lowering in hamsters correlated with the magnitude of hepatic gene expression changes. Importantly, the presence of PPARgamma agonism did not affect the relationship between hepatic gene expression and lipid lowering. Taken together, these data suggest that PPARalpha/gamma agonists, such as TZD18, affect lipid homeostasis, leading to an antiatherogenic plasma lipid profile. Agents with these properties may provide favorable means for treatment of type 2 diabetes and dyslipidemia and the prevention of atherosclerotic cardiovascular disease.
Endocrinology 05/2004; 145(4):1640-8. · 4.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A rapid in vitro assay was developed for monitoring protein-mediated cholesterol monomerization from bile acid aggregates. This assay uses a fluorescent cholesterol analog, 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3 beta-ol (NBD-cholesterol), which was shown to be absorbed by hamster in a fashion similar to cholesterol. The fluorescence of aggregates of NBD-cholesterol was strongly quenched in 2.5 mM of taurocholic acid. Addition of proteins from enterocytes of hamster small intestine led to a time- and dose-dependent dequenching of NBD-cholesterol fluorescence. Comparable dequenching can be detected with SDS and appears to involve monomerization of the NBD-cholesterol. Purification of enterocyte extract by sequential chromatography revealed an approximately 140-kDa protein complex (p140) able to mediate the monomerization of NBD-cholesterol. Each p140 complex mediated monomerization of 2.7 NBD-cholesterol molecules. The p140 complex appeared to be formed by dimerization of two approximately 58-kDa molecules since SDS-PAGE revealed a single dominant band at 58 kDa (p58). Protein sequence analysis suggested that p58 is protein-disulfide isomerase (PDI), and this conclusion was confirmed by cloning of hamster PDI, and detection of PDI enzyme activity in the purified fraction. Additional studies with either pure PDI or lysates of cells transfected with hamster PDI showed that PDI by itself was not sufficient for monomerizing cholesterol. Further, despite a similar mobility on SDS-PAGE (approximately 58 kDa), the p140 complex appeared approximately 45-kDa larger than pure PDI (approximately 95 kDa) when analyzed by a gel-filtration chromatography. The p140 complex may thus contain an unidentified molecule(s) in addition to PDI that may contribute importantly to cholesterol monomerization.
Biochimica et Biophysica Acta 05/2002; 1581(3):100-8. · 4.66 Impact Factor
-
Anne Hermanowski-Vosatka,
David Gerhold,
Steven S. Mundt,
Vilert A. Loving,
Meiqing Lu,
Yuli Chen,
Alex Elbrecht,
Margaret Wu,
Thomas Doebber,
Linda Kelly,
Denise Milot, Qiu Guo,
Pei-Ran Wang,
Marc Ippolito,
Yu-Sheng Chao,
Samuel D. Wright,
Rolf Thieringer
[show abstract]
[hide abstract]
ABSTRACT: 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) is an enzyme that converts cortisone to the active glucocorticoid, cortisol. Cortisol–cortisone interconversion plays a key role in the regulation of glucose metabolism, since mice deficient in 11βHSD1 are resistant to diet-induced hyperglycemia. Peroxisome proliferator activator receptors (PPAR) are key regulators of glucose and lipid homeostasis. We observed a striking downregulation of murine hepatic 11βHSD1 expression and activity after chronic treatment of wild-type mice with PPARα agonists, while 11βHSD1 in the livers of PPARα knockout mice, or in mice treated for only 7 h with PPARα agonists, was unaltered. Our results are the first to show PPARα agonists can affect glucocorticoid metabolism in the liver by altering 11βHSD1 expression after chronic treatment. Regulation of active glucocorticoid levels in the liver by PPARα agonists may in turn affect glucose metabolism, consistent with reports of their antidiabetic effects.
Biochemical and Biophysical Research Communications.
-
Qiu Guo,
Soumya P Sahoo,
Pei-Ran Wang,
Denise P Milot,
Marc C Ippolito,
Margaret S Wu,
Joanne Baffic,
Chhabi Biswas,
Melba Hernandez,
My-Hanh Lam, [......],
Karen L Macnaul,
Gaochao Zhou,
Ranjit Desai,
James V Heck,
Thomas W Doebber,
Joel P Berger,
David E Moller,
Carl P Sparrow,
Yu-Sheng Chao,
Samuel D Wright
