The Experts below are selected from a list of 216 Experts worldwide ranked by ideXlab platform
Daniel Romo - One of the best experts on this subject based on the ideXlab platform.
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practical catalytic asymmetric synthesis of β lactones via a sequential ketene dimerization hydrogenation process inhibitors of the thioesterase domain of fatty acid synthase
Journal of Organic Chemistry, 2006Co-Authors: Vikram C Purohit, Robyn D Richardson, Jeffrey W Smith, Daniel RomoAbstract:The recent finding that the FDA-approved Antiobesity Agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-beta-lactones. The well-documented up-regulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-beta-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-beta-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent alpha-epimerization and alpha-alkylation or acylation led to trans-beta-lactones and beta-lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-lactones displayed antagonistic activity (apparent Ki in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis-beta-lactone 3d, displayed an apparent Ki (2.5 +/- 0.5 microM) of only approximately 10-fold lower than that of orlistat (0.28 +/- 0.06 microM). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining.
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practical catalytic asymmetric synthesis of β lactones via a sequential ketene dimerization hydrogenation process inhibitors of the thioesterase domain of fatty acid synthase
Journal of Organic Chemistry, 2006Co-Authors: Vikram C Purohit, Robyn D Richardson, Jeffrey W Smith, Daniel RomoAbstract:The recent finding that the FDA-approved Antiobesity Agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-β-lactones. The well-documented up-regulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-β-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-β-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent α-epimerization and α-alkylation or acylation led to trans-β-lactones and β-lactones bearing α-quaternary carbons, respectively. Several of the ketene dimers a...
Vikram C Purohit - One of the best experts on this subject based on the ideXlab platform.
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practical catalytic asymmetric synthesis of β lactones via a sequential ketene dimerization hydrogenation process inhibitors of the thioesterase domain of fatty acid synthase
Journal of Organic Chemistry, 2006Co-Authors: Vikram C Purohit, Robyn D Richardson, Jeffrey W Smith, Daniel RomoAbstract:The recent finding that the FDA-approved Antiobesity Agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-beta-lactones. The well-documented up-regulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-beta-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-beta-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent alpha-epimerization and alpha-alkylation or acylation led to trans-beta-lactones and beta-lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-lactones displayed antagonistic activity (apparent Ki in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis-beta-lactone 3d, displayed an apparent Ki (2.5 +/- 0.5 microM) of only approximately 10-fold lower than that of orlistat (0.28 +/- 0.06 microM). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining.
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practical catalytic asymmetric synthesis of β lactones via a sequential ketene dimerization hydrogenation process inhibitors of the thioesterase domain of fatty acid synthase
Journal of Organic Chemistry, 2006Co-Authors: Vikram C Purohit, Robyn D Richardson, Jeffrey W Smith, Daniel RomoAbstract:The recent finding that the FDA-approved Antiobesity Agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-β-lactones. The well-documented up-regulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-β-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-β-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent α-epimerization and α-alkylation or acylation led to trans-β-lactones and β-lactones bearing α-quaternary carbons, respectively. Several of the ketene dimers a...
M D Meglasson - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological activity of aminoguanidine and diaminoguanidine analogues of the antidiabetic Antiobesity Agent 3 guanidinopropionic acid
Journal of Medicinal Chemistry, 2001Co-Authors: Valerie A Vaillancourt, Scott D Larsen, Steven P Tanis, J E Burr, M A Connell, Michele M Cudahy, B R Evans, P V Fisher, Paul D May, M D MeglassonAbstract:3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as α-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidi...
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synthesis and biological activity of analogues of the antidiabetic Antiobesity Agent 3 guanidinopropionic acid discovery of a novel aminoguanidinoacetic acid antidiabetic Agent
Journal of Medicinal Chemistry, 2001Co-Authors: Scott D Larsen, M A Connell, Michele M Cudahy, B R Evans, Paul D May, M D Meglasson, Theresa J Osullivan, Heinrich J Schostarez, J C Sih, F C StevensAbstract:3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate 4. In an effort to identify novel entities that maintain antidiabetic potency without susceptibility to creatine-like metabolism, an analogue program was undertaken to explore the effects of various structural modifications, including homologation, simple substitution, single atom mutations, and bioisosteric replacements for the guanidine and carboxylic acid. Overall, the scope of activity encompassed by the set of new analogues proved to be exceedingly narrow. Notable exceptions demonstrating equivalent or improved antidiabetic activity included the α-amino derivative 29, aminopyridine 47, isothioure...
Arthur A Hancock - One of the best experts on this subject based on the ideXlab platform.
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in vitro optimization of structure activity relationships of analogues of a 331440 combining radioligand receptor binding assays and micronucleus assays of potential Antiobesity histamine h3 receptor antagonists
Basic & Clinical Pharmacology & Toxicology, 2004Co-Authors: Arthur A Hancock, Kathleen M Krueger, Ramin Faghih, Eugene N Bush, Marilyn S Diehl, Gopala Krishna, Thomas R Miller, Phong Nguyen, John K Pratt, Marlon D CowartAbstract:Abstract: A-331440 {4′-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile}, a potent and selective antagonist of histamine H3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo. Because this compound has highly favourable properties and potential as an Antiobesity Agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A-331440 for H3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A-331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A-331440 for H3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono- and di-fluorinated analogues (A-417022 [4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy}-3′-fluoro-1,1′-biphenyl-4-carbonitrile] and A-423579 [4′-{3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]-propoxy}-3′,5′-difluoro-1,1′-biphenyl-4-carbonitrile], respectively) were found to bind to H3 receptors at least as potently as A-331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A-331440 represented the most potent and potentially safest compounds for further evaluation as Antiobesity leads. Preliminary findings with one of these examples, A-417022, in a mouse model of obesity are presented.
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Antiobesity effects of a 331440 a novel non imidazole histamine h3 receptor antagonist
European Journal of Pharmacology, 2004Co-Authors: Arthur A Hancock, Timothy A Esbenshade, Kathleen M Krueger, Ramin Faghih, Youssef L Bennani, Eugene N Bush, Victoria Knoureksegel, Merrill Nuss, Peer B. Jacobson, Robin ShapiroAbstract:Abstract Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H 3 receptors regulate release of histamine and other neurotransmitters, and histamine H 3 receptor antagonists enhance neurotransmitter release. A-331440 {4′-[3-(3( R )-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile} is a histamine H 3 receptor antagonist which binds potently and selectively to both human and rat histamine H 3 receptors ( K i ≤25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H 3 receptor antagonist, A-331440, has potential as an Antiobesity Agent.
Scott D Larsen - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological activity of aminoguanidine and diaminoguanidine analogues of the antidiabetic Antiobesity Agent 3 guanidinopropionic acid
Journal of Medicinal Chemistry, 2001Co-Authors: Valerie A Vaillancourt, Scott D Larsen, Steven P Tanis, J E Burr, M A Connell, Michele M Cudahy, B R Evans, P V Fisher, Paul D May, M D MeglassonAbstract:3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as α-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidi...
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synthesis and biological activity of analogues of the antidiabetic Antiobesity Agent 3 guanidinopropionic acid discovery of a novel aminoguanidinoacetic acid antidiabetic Agent
Journal of Medicinal Chemistry, 2001Co-Authors: Scott D Larsen, M A Connell, Michele M Cudahy, B R Evans, Paul D May, M D Meglasson, Theresa J Osullivan, Heinrich J Schostarez, J C Sih, F C StevensAbstract:3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate 4. In an effort to identify novel entities that maintain antidiabetic potency without susceptibility to creatine-like metabolism, an analogue program was undertaken to explore the effects of various structural modifications, including homologation, simple substitution, single atom mutations, and bioisosteric replacements for the guanidine and carboxylic acid. Overall, the scope of activity encompassed by the set of new analogues proved to be exceedingly narrow. Notable exceptions demonstrating equivalent or improved antidiabetic activity included the α-amino derivative 29, aminopyridine 47, isothioure...