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1.
J Org Chem ; 76(17): 7048-55, 2011 Sep 02.
Article in English | MEDLINE | ID: mdl-21736359

ABSTRACT

Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11ß-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11ß-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/chemical synthesis , Piperazines/chemical synthesis , Propanols/chemical synthesis , 11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 1/chemistry , Administration, Oral , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacology , Propanols/chemistry , Propanols/pharmacology
2.
J Phys Chem B ; 112(35): 11071-8, 2008 Sep 04.
Article in English | MEDLINE | ID: mdl-18693699

ABSTRACT

The solvation of carbohydrates in N, N'-dialkylimidazolium ionic liquids (ILs) was investigated by means of 13C and 35/37Cl NMR relaxation and 1H pulsed field gradient stimulated echo (PFG-STE) diffusion measurements. Solutions of model sugars in 1- n-butyl-3-methylimidazolium chloride ([C4mim]Cl), 1-allyl-3-methylimidazolium chloride ([CC2mim]Cl), and 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) were studied to evaluate the effects of cation and anion structure on the solvation mechanism. In all cases, the changes in the relaxation times of carbon nuclei of the IL cations as a function of carbohydrate concentration are small and consistent with the variation in solution viscosities. Conversely, the 35/37Cl and 13C relaxation rates of chloride ions and acetate ion carbons, respectively, have a strong dependency on sugar content. For [C2mim][OAc], the correlation times estimated from 13C relaxation data for both ions reveal that, as the carbohydrate concentration increases, the reorientation rate of the anion decreases faster than that of the cation. Although not as marked as the variations observed in the relaxation data, similar trends were obtained from the analysis of cation and, in the case of [C2mim][OAc], anion self-diffusion coefficients of the sugar/IL systems. Our results show that the interactions between the IL cation and the solutes are nonspecific, confirm that the process is governed by the interactions between the IL anion and the carbohydrate, and, more importantly, indicate no change in the solvation mechanism regardless of the structure of the anion.

3.
J Org Chem ; 72(3): 1043-6, 2007 Feb 02.
Article in English | MEDLINE | ID: mdl-17253833

ABSTRACT

This work describes two distinct routes to prepare pyrazolo[1,5-alpha]pyrimidin-7-ones and two distinct routes to prepare pyrazolo[1,5-alpha]pyrimidin-5-ones. Use of 1,3-dimethyluracil as the electrophile in the preparation of the pyrimidin-5-one regioisomer represents a correction of previously reported results. Also, a novel reaction to prepare this isomer was identified and the reaction mechanism elucidated. This work provides the experimentalist with complimentary synthetic pathways that afford either the pyrimidin-7-one or the pyrimidin-5-one regioisomer.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Pyrazoles/chemistry , Pyrimidinones/chemistry , Isomerism , Models, Chemical , Schistosomicides/chemical synthesis , Uracil/analogs & derivatives , Uracil/chemistry
4.
J Pharm Biomed Anal ; 31(6): 1211-22, 2003 Apr 10.
Article in English | MEDLINE | ID: mdl-12667937

ABSTRACT

The degradation product of ezlopitant was isolated from low specific activity material and identified by solution phase hydrogen/deuterium (H/D) exchange and electrospray ionization tandem mass spectrometry (ESI/MS/MS) to be an isopropyl peroxide analog of ezlopitant. The structure of the degradant was further confirmed by nuclear magnetic resonance (NMR) spectroscopy utilizing complete 1H and 13C assignments. Studies were also performed to identify the factors responsible for the oxidative degradation of ezlopitant, which included salt form, storage conditions and salt formation solvent. Of all the variable studies over a 3 weeks period, only a change in the salt form prevented this oxidative degradation.


Subject(s)
Benzylamines/analysis , Benzylamines/metabolism , Bridged Bicyclo Compounds, Heterocyclic/analysis , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Spectrometry, Mass, Electrospray Ionization/methods , Substance P/antagonists & inhibitors , Benzylamines/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Deuterium , Magnetic Resonance Spectroscopy/methods , Protons
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