Yi-Xin Li
Bristol-Myers Squibb
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Publication
Featured researches published by Yi-Xin Li.
Journal of Medicinal Chemistry | 2010
Jun Li; Lawrence J. Kennedy; Yan Shi; Shiwei Tao; Xiang-Yang Ye; Stephanie Y. Chen; Ying Wang; Andres S. Hernandez; Wei Wang; Pratik Devasthale; Sean Chen; Zhi Lai; Hao Zhang; Shung Wu; Rebecca A. Smirk; Scott A. Bolton; Denis E. Ryono; Huiping Zhang; Ngiap-Kie Lim; Bang-Chi Chen; Kenneth T. Locke; Kevin O’Malley; Litao Zhang; Rai Ajit Srivastava; Bowman Miao; Daniel Meyers; Hossain Monshizadegan; Debra Search; Denise Grimm; Rongan Zhang
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.
Journal of Medicinal Chemistry | 2014
Dean A. Wacker; Ying Wang; Matthias Broekema; Karen A. Rossi; Steven O’Connor; Zhenqiu Hong; Ginger Wu; Sarah E. Malmstrom; Chen-Pin Hung; Linda LaMarre; Anjaneya Chimalakonda; Lisa Zhang; Li Xin; Hong Cai; Cuixia Chu; Stephanie Boehm; Jacob Zalaznick; Randolph Ponticiello; Larisa Sereda; Songping Han; Rachel Zebo; Bradley A. Zinker; Chiuwa Emily Luk; Richard Wong; Gerry Everlof; Yi-Xin Li; Chunyu K. Wu; Michelle Lee; Steven Griffen; Keith J. Miller
G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.
Bioorganic & Medicinal Chemistry Letters | 2011
Haixia Wang; Jeffrey A. Robl; Lawrence G. Hamann; Ligaya M. Simpkins; Rajasree Golla; Yi-Xin Li; Ramakrishna Seethala; Tatyana Zvyaga; David A. Gordon; James J. Li
A series of pyridyl amide/sulfonamide inhibitors of 11β-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme.
Journal of Medicinal Chemistry | 2009
Alexandra A. Nirschl; Yan Zou; Stanley R. Krystek; James C. Sutton; Ligaya M. Simpkins; John A. Lupisella; Joyce E. Kuhns; Ramakrishna Seethala; Rajasree Golla; Paul G. Sleph; Blake C. Beehler; Gary J. Grover; Donald Egan; Aberra Fura; Viral Vyas; Yi-Xin Li; John S. Sack; Kevin Kish; Yongmi An; James A. Bryson; Jack Z. Gougoutas; John D. Dimarco; Robert Zahler; Jacek Ostrowski; Lawrence G. Hamann
A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.
Journal of Medicinal Chemistry | 2013
Pratik Devasthale; Ying Wang; Wei Wang; John Matthew Fevig; Jianxin Feng; Aiying Wang; Tom Harrity; Don Egan; Nathan Morgan; Michael Cap; Aberra Fura; Herbert E. Klei; Kevin Kish; Carolyn Weigelt; Lucy Sun; Paul Levesque; Frederic Moulin; Yi-Xin Li; Robert Zahler; Mark S. Kirby; Lawrence G. Hamann
Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
Bioorganic & Medicinal Chemistry Letters | 2011
Shung C. Wu; David S. Yoon; Janice Chin; Katy Van Kirk; Ramakrishna Seethala; Rajasree Golla; Bin He; Thomas Harrity; Lori Kunselman; Nathan Morgan; Randolph Ponticiello; Joseph R. Taylor; Rachel Zebo; Timothy W. Harper; Wenying Li; Mengmeng Wang; Lisa Zhang; Bogdan Sleczka; Akbar Nayeem; Steven Sheriff; Daniel M. Camac; Paul E. Morin; John G. Everlof; Yi-Xin Li; Cheryl Ferraro; Kasia Kieltyka; Wilson Shou; Marianne Vath; Tatyana Zvyaga; David A. Gordon
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.
Bioorganic & Medicinal Chemistry Letters | 2014
Xiang-Yang Ye; David S. Yoon; Stephanie Y. Chen; Akbar Nayeem; Rajasree Golla; Ramakrishna Seethala; Mengmeng Wang; Timothy W. Harper; Bogdan Sleczka; Atsu Apedo; Yi-Xin Li; Bin He; Mark S. Kirby; David A. Gordon; Jeffrey A. Robl
A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11β-HSD1 enzyme. Optimization of two regions of A, R(1) and R(2) respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11β-HSD1 with a favorable development profile.
Bioorganic & Medicinal Chemistry Letters | 2011
Xiang-Yang Ye; Stephanie Y. Chen; Akbar Nayeem; Rajasree Golla; Ramakrishna Seethala; Mengmeng Wang; Timothy W. Harper; Bogdan Sleczka; Yi-Xin Li; Bin He; Mark S. Kirby; David A. Gordon; Jeffrey A. Robl
Starting from high throughput screening hit 2-adamantyl acetic acid 3, a series of polycyclic acids have been designed and synthesized as novel, potent, and selective inhibitors of human 11β-HSD-1. Structure-activity relationships of two different regions of the chemotype (polycyclic ring and substituents on quaternary carbon) are discussed.
Bioorganic & Medicinal Chemistry Letters | 2011
Wei Wang; Pratik Devasthale; Aiying Wang; Tom Harrity; Don Egan; Nathan Morgan; Michael Cap; Aberra Fura; Herbert E. Klei; Kevin Kish; Carolyn A. Weigelt; Lucy Sun; Paul Levesque; Yi-Xin Li; Robert Zahler; Mark S. Kirby; Lawrence G. Hamann
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice.
Bioorganic & Medicinal Chemistry | 2016
James R. Corte; Tianan Fang; Donald J. P. Pinto; Michael J. Orwat; Alan R. Rendina; Joseph M. Luettgen; Karen A. Rossi; Anzhi Wei; Vidhyashankar Ramamurthy; Joseph E. Myers; Steven Sheriff; Rangaraj Narayanan; Timothy W. Harper; Joanna J. Zheng; Yi-Xin Li; Dietmar Seiffert; Ruth R. Wexler; Mimi L. Quan
Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.