- 3S-Fluoroproline as a probe to monitor proline isomerization during protein folding by 19F-NMR
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Variable-temperature inversion transfer NMR is used to determine the kinetic and thermodynamic parameters of cis-trans isomerization of N-Ac-(3R) and (3S)-fluoroproline-OMe.
- Thomas, Colin A.,Talaty, Erach R.,Bann, James G.
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Read Online
- A Diversity Oriented Synthesis Approach to New 2,3- trans-Substituted l -Proline Analogs as Potential Ligands for the Ionotropic Glutamate Receptors
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Discovery of chemical tools for the ionotropic glutamate receptors continues to be a challenging task. Herein we report a diversity-oriented approach to new 2,3-trans-l-proline analogs whereby we study how the spatial orientation of the distal carboxylate group influences the binding affinity and receptor class and subtype selectivity. In total, 10 new analogs were synthesized and 14 stereoisomers characterized in binding assays at native rat ionotropic glutamate receptors, and at cloned human homomeric kainic acid (KA) receptor subtypes GluK1-3. The study identified isoxazole analogs 3d,e, which displayed selectivity in binding at native N-methyl-d-aspartate (NMDA) receptors over native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KA receptors, in the high nanomolar to low micromolar range. Furthermore, analogs 3i-A/B showed a preference in binding affinity for GluK3 over GluK1,2. Finally, analog 3j displayed high nanomolar affinity for native NMDA receptors as well as for homomeric GluK3 receptors.
- Bunch, Lennart,Kayser, Silke,Nielsen, Birgitte,Pickering, Darryl S.,Poulie, Christian B. M.,Staudt, Markus,Temperini, Piero
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- Stereodivergent Synthesis of 3-Hydroxyprolines and 3-Hydroxypipecolic Acids via Ketoreductase-Catalyzed Dynamic Kinetic Reduction
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We report a practical enzymatic approach for the stereoselective synthesis of hydroxylated cyclic amino acids. Using ketoreductases, cyclic ketoesters are converted with high diastereo- and enantioselectivity to all isomers of 3-hydroxyproline and 3-hydroxypipecolic acid via a dynamic kinetic reduction reaction. This work highlights the ability of enzymes to provide solutions to challenges in stereoselective synthesis. (Figure presented.).
- Prier, Christopher K.,Lo, Michael M.-C.,Li, Hongming,Yasuda, Nobuyoshi
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supporting information
p. 5140 - 5143
(2019/11/03)
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- TRICYCLIC PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Described herein are tricyclic compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.
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- 1-(CYCLOALKYL-CARBONYL)PROLINE DERIVATIVE
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A compound represented by formula (1) (in the formula: ring-D represents a three- to eight-membered hydrocarbon ring; Ra represents an optionally substituted amino C1-6 alkyl group or the like; Rb1 and Rb2 each independently represent a hydrogen atom, a halogen atom, or the like; Rc represents an optionally substituted C6-10 aryl group or the like; Rd represents a hydrogen atom or the like; and ring-Q represents a (hetero)aryl group or the like which may be substituted with a carboxyl group or the like) or a pharmaceutically acceptable salt thereof exhibits an excellent FXIa inhibitory activity, and is useful as a therapeutic agent against thrombosis or the like.
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- N-HYDROXYAMIDE DERIVATIVES POSSESSING ANTIBACTERIAL ACTIVITY
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Described herein are N-hydroxyamlde antibacterial compounds, methods for making the compounds, pharmaceutical compositions containing the compounds and methods of treating bacterial infections utilizing the compounds and pharmaceutical compositions compound of Formula (I): or a salt, solvate ti hydrate thereof, wherein A is (a) eachindicates a point of attachment.
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Page/Page column 33; 39
(2010/02/17)
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- AZA-BENZOFURANYL COMPOUNDS AND METHODS OF USE
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The invention relates to azabenzofuranyl compounds of Formula (I) with anti-cancer and/or anti-inflammatory activity and more specifically to azabenzofuranyl compounds which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
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Page/Page column 125
(2008/06/13)
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- Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications
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A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
- Li, James J.,Sutton, James C.,Nirschl, Alexandra,Zou, Yan,Wang, Haixia,Sun, Chongqing,Pi, Zulan,Johnson, Rebecca,Krystek Jr., Stanley R.,Seethala, Ramakrishna,Golla, Rajasree,Sleph, Paul G.,Beehler, Blake C.,Grover, Gary J.,Fura, Aberra,Vyas, Viral P.,Li, Cindy Y.,Gougoutas, Jack Z.,Galella, Michael A.,Zahler, Robert,Ostrowski, Jacek,Hamann, Lawrence G.
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p. 3015 - 3025
(2008/02/06)
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- Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold
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A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.
- Sun, Chongqing,Robl, Jeffrey A.,Wang, Tammy C.,Huang, Yanting,Kuhns, Joyce E.,Lupisella, John A.,Beehler, Blake C.,Golla, Rajasree,Sleph, Paul G.,Seethala, Ramakrishna,Fura, Aberra,Krystek Jr., Stanley R.,An, Yongmi,Malley, Mary F.,Sack, John S.,Salvati, Mark E.,Grover, Gary J.,Ostrowski, Jacek,Hamann, Lawrence G.
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p. 7596 - 7599
(2007/10/03)
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- BICYCLIC MODULATORS OF ANDROGEN RECEPTOR FUNCTION
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The present invention relates to bicyclic compounds according to formula I, pharmaceutical compositions containing such compounds and methods of using such compounds in the treatment of androgen receptor-associated conditions, such as age-related diseases, for example sarcopenia, wherein R1, R2, R5, X, Y and n are defined herein.
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Page/Page column 17
(2008/06/13)
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- Bicyclic modulators of androgen receptor function
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The invention provides for a pharmaceutical composition capable of modulating the androgen receptor comprising a compound of formula I wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia. Also provided are pharmaceutical compositions containing such compounds and processes for preparing some of the compounds of the invention.
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- BICYCLIC MODULATORS OF ANDROGEN RECEPTOR FUNCTION
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The invention provides compounds according to formula I wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia. Also provided are pharmaceutical compositions containing such compounds and processes for preparing some of the compounds of the invention.
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- Bicyclic modulators of androgen receptor function
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The invention provides compounds of the formula I wherein the substitutents are as described herein. Further provided are methods of using such compounds for the treatment of nuclear hormone receptor-associated conditions, such as age related diseases, for example sarcopenia, and also provided are pharmaceutical compositions containing such compounds.
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- Short, highly efficient syntheses of protected 3-azido- and 4-azidoproline and their precursors
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matrix presented An improved synthesis of protected cis- and trans-3-azido-L-proline and cis- and frans-4-azido-L- and -D-proline is reported. These compounds have been synthesized from the corresponding hydroxyproline precursors using diphenylphosphoryl azide under Mitsunobu conditions. Short, highly efficient syntheses of these precursors are described, based on a new lactone-opening reaction and p-nitrobenzoate hydrolysis under very mild conditions.
- Gomez-Vidal, Jose A.,Silverman, Richard B.
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p. 2481 - 2484
(2007/10/03)
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- Intramolecular Hydrosilylations of β,γ-Unsaturated Acyloxy Silanes. A Convenient Synthesis of (2S,3R)-N-BOC-3-Hydroxyproline Methyl Ester
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A regio- and stereoselective synthesis of hydroxylated carboxylic acids by intramolecular hydrosilylation of β,γ-unsaturated acyloxysilanes has been developed.Application of the methodology in the synthesis of (2S,3R)-3-hydroxy-N-BOC-proline methyl ester is described.
- Sibi, Mukund P.,Christensen, James W.
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p. 6213 - 6216
(2007/10/02)
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