Stephen M. Lynch
Hoffmann-La Roche
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Publication
Featured researches published by Stephen M. Lynch.
Journal of Medicinal Chemistry | 2013
Fernando Padilla; Niala Bhagirath; Shaoqing Chen; Eric Chiao; David Michael Goldstein; Johannes Cornelius Hermann; Jonathan Hsu; Joshua Kennedy-Smith; Andreas Kuglstatter; Cheng Liao; Wenjian Liu; Lee Edwin Lowrie; Kin Chun Luk; Stephen M. Lynch; John Menke; Linghao Niu; Timothy D. Owens; Counde O'yang; Aruna Railkar; Ryan Craig Schoenfeld; Michelle Slade; Sandra Steiner; Yun-Chou Tan; Armando G. Villaseñor; Ce Wang; Jutta Wanner; Wenwei Xie; Daigen Xu; Xiaohu Zhang; Mingyan Zhou
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
Bioorganic & Medicinal Chemistry Letters | 2008
Linda M. Bannwart; David S. Carter; Hai-Ying Cai; Jason Chi-Chung Choy; Robert Greenhouse; Saul Jaime-Figueroa; Pravin Iyer; Clara Jeou Jen Lin; Eun Kyung Lee; Matthew C. Lucas; Stephen M. Lynch; Ann Marie Madera; Amy Geraldine Moore; Kerem Erol Ozboya; Lubica Raptova; Ralf Roetz; Ryan Craig Schoenfeld; Karin Ann Stein; Sandra Steiner; Marzia Villa; Robert James Weikert; Yansheng Zhai
A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.
Bioorganic & Medicinal Chemistry Letters | 2013
Stephen M. Lynch; Javier DeVicente; Johannes C. Hermann; Saul Jaime-Figueroa; Sue Jin; Andreas Kuglstatter; Hongju Li; Allen John Lovey; John Menke; Linghao Niu; Vaishali Patel; Douglas Roy; Michael Soth; Sandra Steiner; Parcharee Tivitmahaisoon; Minh Diem Vu; Calvin Yee
Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
Bioorganic & Medicinal Chemistry Letters | 2013
Saul Jaime-Figueroa; Javier de Vicente; Johannes C. Hermann; Alam Jahangir; Sue Jin; Andreas Kuglstatter; Stephen M. Lynch; John Menke; Linghao Niu; Vaishali Patel; Ada Shao; Michael Soth; Minh Diem Vu; Calvin Yee
We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.
Bioorganic & Medicinal Chemistry Letters | 2010
Matthew C. Lucas; Robert James Weikert; David S. Carter; Hai-Ying Cai; Robert Greenhouse; Pravin Iyer; Clara Jeou Jen Lin; Eun Kyung Lee; Ann Marie Madera; Amy Geraldine Moore; Kerem Erol Ozboya; Ryan Craig Schoenfeld; Sandra Steiner; Yansheng Zhai; Stephen M. Lynch
Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.
Archive | 2009
Robert Than Hendricks; Johannes Cornelius Hermann; Rama K. Kondru; Yan Lou; Stephen M. Lynch; Timothy D. Owens; Michael Soth
Archive | 2011
Robert Than Hendricks; Johannes Cornelius Hermann; Saul Jaime-Figueroa; Rama K. Kondru; Yan Lou; Stephen M. Lynch; Timothy D. Owens; Michael Soth; Calvin Yee
Archive | 2011
Robert Than Hendricks; Johannes Cornelius Hermann; Rama K. Kondru; Yan Lou; Stephen M. Lynch; Timothy D. Owens; Michael Soth; Calvin Yee
Archive | 2006
Robert Greenhouse; Saul Jaime-Figueroa; Stephen M. Lynch; Lubica Raptova; Karin Ann Stein; Robert James Weikert
Archive | 2009
Pravin S. Iyer; Clara Jeou Jen Lin; Matthew C. Lucas; Stephen M. Lynch; Ann Marie Madera; Kerem Erol Ozboya; Ryan Craig Schoenfeld; Robert James Weikert