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Dive into the research topics where Lawrence J. Kennedy is active.

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Featured researches published by Lawrence J. Kennedy.


Journal of Medicinal Chemistry | 2008

(3R,5S,E)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential

Saleem Ahmad; Cort S. Madsen; Philip D. Stein; Evan B. Janovitz; Christine Huang; Khehyong Ngu; Sharon N. Bisaha; Lawrence J. Kennedy; Bang-Chi Chen; Rulin Zhao; Doree Sitkoff; Hossain Monshizadegan; Xiaohong Yin; Carol S. Ryan; Rongan Zhang; Mary R. Giancarli; Eileen Bird; Ming Chang; Xing Chen; Robert Setters; Debra Search; Shaobin Zhuang; Van Nguyen-Tran; Carolyn A. Cuff; Thomas Harrity; Celia D'Arienzo; Tong Li; Richard A. Reeves; Michael A. Blanar; Joel C. Barrish

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.


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.


Organic Letters | 2008

A Synthesis of N-Bridged 5,6-Bicylic Pyridines via A Mild Cyclodehydration Using the Burgess Reagent and Discovery of A Novel Carbamylsulfonylation Reaction

Jie Jack Li; James J. Li; Jun Li; Ashok Trehan; Henry S. Wong; Subramanian Krishnananthan; Lawrence J. Kennedy; Qi Gao; Alicia Ng; Jeffrey A. Robl; Balu Balasubramanian; Bang-Chi Chen

Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct.


ACS Medicinal Chemistry Letters | 2014

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1).

Jun Li; Lawrence J. Kennedy; Haixia Wang; James J. Li; Steven J. Walker; Zhenqiu Hong; Stephen P. O’Connor; Akbar Nayeem; Daniel M. Camac; Paul E. Morin; Steven Sheriff; Mengmeng Wang; Timothy W. Harper; Rajasree Golla; Ramakrishna Seethala; Thomas Harrity; Randolph Ponticiello; Nathan Morgan; Joseph R. Taylor; Rachel Zebo; David A. Gordon; Jeffrey A. Robl

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.


ACS Medicinal Chemistry Letters | 2016

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist

Yan Shi; Jun Li; Lawrence J. Kennedy; Shiwei Tao; Andres S. Hernandez; Zhi Lai; Sean Chen; Henry Wong; Juliang Zhu; Ashok Trehan; Ngiap-Kie Lim; Huiping Zhang; 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; Thomas Harrity; Lori Kunselman; Michael Cap; Jodi K. Muckelbauer; Chiehying Chang; Stanley R. Krystek; Yi-Xin Li

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.


Archive | 2008

Triazolopyridine 11-beta hydroxysteroid dehydrogenase type i inhibitors

Jun Li; Jeffrey A. Robl; James J. Li; Lawrence J. Kennedy; Haixia Wang; Jie Jack Li; Chenkou Wei; Michael A. Galella


Archive | 2008

Fused heterocyclic 11-beta-hydroxysteroid dehydrogenase type i inhibitors

Jun Li; James J. Li; Stephen P. O'connor; Haixia Wang; Lawrence J. Kennedy; Jeffrey A. Robl; Lawrence G. Hamann


Archive | 2007

Triazine 11-beta hydroxysteroid dehydrogenase type 1 inhibitors

Jun Li; Jeffrey A. Robl; Lawrence J. Kennedy


Tetrahedron Letters | 2010

A mild and general one-pot preparation of cyanoethyl-protected tetrazoles

Lawrence J. Kennedy

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Jun Li

Bristol-Myers Squibb

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Yan Shi

Bristol-Myers Squibb

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