- ACETYLENE DERIVATIVES AS STEAROYL COA DESATURASE INHIBITORS
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The present invention provides Stearoyl CoA Desaturase (SCD) inhibitors, hi particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by Stearoyl CoA Desaturase 1 (SCD 1) inhibitors. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by Stearoyl CoA Desaturase (SCD) inhibitors.
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Page/Page column 50-51
(2008/12/05)
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- 4-Amino-5-aryl-6-arylethynylpyrimidines: Structure-activity relationships of non-nucleoside adenosine kinase inhibitors
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A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.
- Matulenko, Mark A.,Paight, Ernest S.,Frey, Robin R.,Gomtsyan, Arthur,DiDomenico Jr., Stanley,Jiang, Meiqun,Lee, Chih-Hung,Stewart, Andrew O.,Yu, Haixia,Kohlhaas, Kathy L.,Alexander, Karen M.,McGaraughty, Steve,Mikusa, Joseph,Marsh, Kennan C.,Muchmore, Steven W.,Jakob, Clarissa L.,Kowaluk, Elizabeth A.,Jarvis, Michael F.,Bhagwat, Shripad S.
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p. 1586 - 1605
(2008/02/01)
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- DOPAMINE D4 RECEPTOR LIGANDS
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Described herein are D4 receptor-selective compounds of the formula: STR1 wherein R 1 is selected from H and an acid labile protecting group; and R 2 and R 3 are independently selected from H, radioisotopic halo, loweralkoxy and tri(loweralkyl)tin; and salts, solvates or hydrates thereof.Also described is the use of these compounds as pharmaceuticals to treat indications for which a dopamine D4 receptor antagonist is indicated. Radiolabeled compounds are useful particularly to image localization of D4 receptor in the human brain, and can therefore aid in the diagnosis of schizophrenia and other medical conditions in which the D4 receptor is implicated.
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