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Dive into the research topics where Michelle Kasem is active.

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Featured researches published by Michelle Kasem.


Journal of Medicinal Chemistry | 2012

(1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (MK-1903): a potent GPR109a agonist that lowers free fatty acids in humans.

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

Complementary asymmetric routes to (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate.

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

Potent tricyclic pyrazole tetrazole agonists of the nicotinic acid receptor (GPR109a)

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

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists

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

Tetrahydroquinoline-based tricyclic amines as potent and selective agonists of the 5-HT2C receptor

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

Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor

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

Modulators of the sphingosine-1-phosphate (s1p) receptor useful for the treatment of disorders related thereto

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

Complementary asymmetric routes to fused tricyclic (R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolines and (R)-1,2,3,4,5,5a,6,7-octahydro-[1,4]diazepino[1,2-a]quinolines

Thomas O. Schrader; Michelle Kasem; Qi Sun; Chunrui Wu; Albert S. Ren; Graeme Semple


Archive | 2015

5-ht2c receptor agonists and compositions and methods of use

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

Processes for the preparation of S1P1 receptor modulators and crystalline forms thereof

Robert M. Jones; Daniel J. Buzard; Tawfik Gharbaoui; Benjamin R. Johnson; Michelle Kasem; Thomas O. Schrader; Scott Stirn

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