Michelle Kasem
Arena Pharmaceuticals, Inc.
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Publication
Featured researches published by Michelle Kasem.
Journal of Medicinal Chemistry | 2012
P. Douglas Boatman; Brett Lauring; Thomas O. Schrader; Michelle Kasem; Benjamin R. Johnson; Philip J. Skinner; Jae-Kyu Jung; Jerry Xu; Martin C. Cherrier; Peter J. Webb; Graeme Semple; Carleton R. Sage; Jens Knudsen; Ruoping Chen; Wen-Lin Luo; Luzelena Caro; Josee Cote; Eseng Lai; John A. Wagner; Andrew K. Taggart; Ester Carballo-Jane; Milton L. Hammond; Steven L. Colletti; James R. Tata; Daniel T. Connolly; M. Gerard Waters; Jeremy G. Richman
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
Organic Letters | 2012
Thomas O. Schrader; Benjamin R. Johnson; Luis Lopez; Michelle Kasem; Tawfik Gharbaoui; Dipanjan Sengupta; Daniel J. Buzard; Christine Basmadjian; Robert M. Jones
Two distinct and scalable enantioselective approaches to the tricyclic indole (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate, an important synthon for a preclinical S1P(1) receptor agonist, are reported. Route 1 employs a modified version of Smiths modular 2-substituted indole synthesis as the key transformation. Route 2 involves a highly enantioselective CuH-catalyzed 1,4-hydrosilylation as the stereodefining step. Both routes can be performed without chromatography to provide multigram quantities of the tricycle in ≥98% ee.
Bioorganic & Medicinal Chemistry Letters | 2010
P. Douglas Boatman; Thomas O. Schrader; Michelle Kasem; Benjamin R. Johnson; Philip J. Skinner; Jae-Kyu Jung; Jerry Xu; Martin C. Cherrier; Peter J. Webb; Graeme Semple; Carleton R. Sage; Jens Knudsen; Ruoping Chen; Andrew K.P. Taggart; Ester Carballo-Jane; Jeremy G. Richman
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.
ACS Medicinal Chemistry Letters | 2014
Daniel J. Buzard; Luis Lopez; Jeanne V. Moody; Andrew M. Kawasaki; Thomas O. Schrader; Michelle Kasem; Ben Johnson; Xiuwen Zhu; Lars Thoresen; Sun Hee Kim; Tawfik Gharbaoui; Dipanjan Sengupta; Lorene Calvano; Ashwin M. Krishnan; Yinghong Gao; Graeme Semple; Jeff Edwards; Jeremy Barden; Michael M. Morgan; Khawja A. Usmani; Chuan Chen; Abu Sadeque; Weichao Chen; Ronald Christopher; Jayant Thatte; Lixia Fu; Michelle Solomon; Kevin Whelan; Hussien A. Al-Shamma; Joel Gatlin
S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.
Bioorganic & Medicinal Chemistry Letters | 2016
Thomas O. Schrader; Michelle Kasem; Albert S. Ren; Konrad Feichtinger; Bilal Al Doori; Jing Wei; Chunrui Wu; Huong T. Dang; Minh Le; Joel Gatlin; Kelli Chase; Jenny Dong; Kevin Whelan; Carleton R. Sage; Andrew J. Grottick; Graeme Semple
The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
Bioorganic & Medicinal Chemistry Letters | 2015
Daniel J. Buzard; Thomas O. Schrader; Xiuwen Zhu; Juerg Lehmann; Ben Johnson; Michelle Kasem; Sun Hee Kim; Andrew M. Kawasaki; Luis Lopez; Jeanne V. Moody; Sangdon Han; Yinghong Gao; Jeff Edwards; Jeremy Barden; Jayant Thatte; Joel Gatlin; Robert M. Jones
Archive | 2010
Robert M. Jones; Daniel J. Buzard; Thomas O. Schrader; Michelle Kasem; Xiuwen Zhu; Benjamin R. Johnson; Juerg Lehmann; Sangdon Han; Andrew M. Kawasaki
Tetrahedron Letters | 2016
Thomas O. Schrader; Michelle Kasem; Qi Sun; Chunrui Wu; Albert S. Ren; Graeme Semple
Archive | 2015
Graeme Semple; Dominic P. Behan; Konrad Feichtinger; Alan Glicklich; Andrew J. Grottick; Maria Matilde Sanchez Kam; Michelle Kasem; Juerg Lehmann; Albert S. Ren; Thomas O. Schrader; William R. Shanahan; Amy Siu-Ting Wong; Xiuwen Zhu
Archive | 2011
Robert M. Jones; Daniel J. Buzard; Tawfik Gharbaoui; Benjamin R. Johnson; Michelle Kasem; Thomas O. Schrader; Scott Stirn