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Dive into the research topics where Joseph A. Tino is active.

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Featured researches published by Joseph A. Tino.


Journal of Pharmacology and Experimental Therapeutics | 2009

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

Soratree Charoenthongtrakul; Derek J. Giuliana; Kenneth A. Longo; Elizabeth Govek; Anna Nolan; Samantha Gagne; Kristen Morgan; Jeffrey Hixon; Neil Flynn; Brian J. Murphy; Andres S. Hernandez; Jun Li; Joseph A. Tino; David A. Gordon; Peter S. DiStefano; Brad J. Geddes

The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.


Journal of Pharmacology and Experimental Therapeutics | 2008

Novel Peroxisome Proliferator-Activated Receptor α Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist

Ranjan Mukherjee; Kenneth T. Locke; Bowman Miao; Daniel Meyers; Hossain Monshizadegan; Rongan Zhang; Debra Search; Denise Grimm; Michael Flynn; Kevin M. O'Malley; Litao Zhang; Jun Li; Yan Shi; Lawrence J. Kennedy; Michael A. Blanar; Peter T. W. Cheng; Joseph A. Tino; Rai Ajit Srivastava

The first generation peroxisome proliferator-activated receptor (PPAR) α agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARα agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARα-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARα than human PPARα; therefore, they were tested in PPARα-humanized mice that do not express murine PPARα but express human PPARα selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARα in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARα agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.


Journal of Medicinal Chemistry | 2010

Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453).

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.


Bioorganic & Medicinal Chemistry Letters | 2014

Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases.

Qing Shi; Andrew J. Tebben; Alaric J. Dyckman; Hedy Li; Chunjian Liu; James Lin; Steve Spergel; James R. Burke; Kim W. McIntyre; Gilbert C. Olini; Joann Strnad; Neha Surti; Jodi K. Muckelbauer; Chiehying Chang; Yongmi An; Lin Cheng; Qian Ruan; Katerina Leftheris; Percy H. Carter; Joseph A. Tino; George V. De Lucca

Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.


Bioorganic & Medicinal Chemistry Letters | 2015

Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton's tyrosine kinase (BTK) and Janus kinase 2 (JAK2).

Qingjie Liu; Douglas G. Batt; Jonathan Lippy; Neha Surti; Andrew J. Tebben; Jodi K. Muckelbauer; Lin Chen; Yongmi An; Chiehying Chang; Matt Pokross; Zheng Yang; Haiqing Wang; James R. Burke; Percy H. Carter; Joseph A. Tino

Four series of disubstituted carbazole-1-carboxamides were designed and synthesised as inhibitors of Brutons tyrosine kinase (BTK). 4,7- and 4,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of BTK, while 3,7- and 3,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of Janus kinase 2 (JAK2).


Chemical Biology & Drug Design | 2011

X-Ray Crystal Structure of Bone Marrow Kinase in the X Chromosome: A Tec Family Kinase

Jodi K. Muckelbauer; John S. Sack; Nazia Ahmed; James R. Burke; ChiehYing Y. Chang; Mian Gao; Joseph A. Tino; Dianlin Xie; Andrew J. Tebben

Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton’s tyrosine kinase and IL‐2‐inducible T‐cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X‐ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 Å resolution and PP2 at 1.9 Å resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well‐ordered protein conformation that includes an open/extended activation loop and a stabilized DFG‐motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG‐motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.


Journal of Medicinal Chemistry | 2016

Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7-(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177)

George V. De Lucca; Qing Shi; Qingjie Liu; Douglas G. Batt; Myra Beaudoin Bertrand; Rick Rampulla; Arvind Mathur; Lorell Discenza; Celia D’Arienzo; Jun Dai; Mary T. Obermeier; Rodney Vickery; Yingru Zhang; Zheng Yang; Punit Marathe; Andrew J. Tebben; Jodi K. Muckelbauer; ChiehYing J. Chang; Huiping Zhang; Kathleen M. Gillooly; Tracy L. Taylor; Mark A. Pattoli; Stacey Skala; Daniel W. Kukral; Kim W. McIntyre; Luisa Salter-Cid; Aberra Fura; James R. Burke; Joel C. Barrish; Percy H. Carter

Brutons tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.


Bioorganic & Medicinal Chemistry Letters | 2010

Synthesis and structure–activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel, potent PPARα selective activators- PPARα and PPARγ selectivity modulation

Xiang-Yang Ye; Stephanie Y. Chen; Hao Zhang; Kenneth T. Locke; Kevin O’Malley; Litao Zhang; Raijit Srivastava; Bowman Miao; Daniel Meyers; Hossain Monshizadegan; Debra Search; Denise Grimm; Rongan Zhang; Jonathan Lippy; Celeste Twamley; Jodi K. Muckelbauer; Chiehying Chang; Yongmi An; Vinayak Hosagrahara; Lisa Zhang; T.-J. Yang; Ranjan Mukherjee; Peter T. W. Cheng; Joseph A. Tino

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.


Bioorganic & Medicinal Chemistry Letters | 1993

Differences in antiviral activities for isomers of a fluorinated cyclobutane nucleoside analog

Gregory D. Vite; Joseph A. Tino; Robert Zahler; V. Goodfellow; Anne V. Tuomari; McGeever-Rubin B; Field Ak

Isomeric fluorinated cyclobutane nucleoside analogs (±)-2 and (±)-3 were prepared via multi-step syntheses. Compound 2 is a potent inhibitor of herpes viruses in cell culture assays, while the configurational isomer 3 is devoid of antiviral activity.


Bioorganic & Medicinal Chemistry Letters | 2008

(D)-2-tert-Butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid: synthesis and incorporation into the growth hormone secretagogues.

Jun Li; Stephanie Y. Chen; Brian J. Murphy; Neil Flynn; Ramakrishna Seethala; Dorothy Slusarchyk; Mujing Yan; Paul G. Sleph; Hongjian Zhang; William G. Humphreys; William R. Ewing; Jeffrey A. Robl; David A. Gordon; Joseph A. Tino

The first enantioselective synthesis of (D)-2-tert-butoxycarbonylamino-5,5-difluoro-5-phenyl-pentanoic acid 3 was achieved. The incorporation of the titled compound into growth hormone secretagogue (GHS) compounds resulted in new analogs 10 and 16, both of which had significantly increased in vitro potency. The compound 10 also showed improved in vivo efficacy as well as pharmacokinetic properties in rat models.

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Jun Li

Bristol-Myers Squibb

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Yan Shi

Bristol-Myers Squibb

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