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Dive into the research topics where Javed Khan is active.

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Featured researches published by Javed Khan.


Journal of Pharmacology and Experimental Therapeutics | 2014

Pharmacologic Profile of the Adnectin BMS-962476, a Small Protein Biologic Alternative to PCSK9 Antibodies for Low-Density Lipoprotein Lowering.

Tracy S. Mitchell; Ginger Chao; Doree Sitkoff; Fred Lo; Hossain Monshizadegan; Daniel Meyers; Simon Low; Katie A. Russo; Rose DiBella; Fabienne M. Denhez; Mian Gao; Joseph E. Myers; Gerald J. Duke; Mark R. Witmer; Bowman Miao; Siew P. Ho; Javed Khan; Rex A. Parker

Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low-density lipoprotein (LDL) in cardiovascular disease, although seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III–domain and engineered for high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar affinity to human. The X-ray cocrystal structure of PCSK9 with a progenitor Adnectin shows ∼910 Å2 of PCSK9 surface covered next to the LDL receptor binding site, largely by residues of a single loop of the Adnectin. In hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels. In genomic transgenic mice, BMS-962476 potently reduced free human PCSK9 (ED50 ∼0.01 mg/kg) followed by ∼2-fold increases in total PCSK9 before return to baseline. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently downregulated, following which LDL and total PCSK9 returned to baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL and liver cholesterol metabolism and characterize BMS-962476 as a potent and efficacious PCSK9 inhibitor.


Journal of Medicinal Chemistry | 2014

Discovery of the CCR1 antagonist, BMS-817399, for the treatment of rheumatoid arthritis.

Joseph B. Santella; Daniel S. Gardner; John V. Duncia; Hong Wu; Murali T. G. Dhar; Cullen L. Cavallaro; Andrew J. Tebben; Percy H. Carter; Joel C. Barrish; Melissa Yarde; Stephanie W. Briceno; Mary Ellen Cvijic; R. Robert Grafstrom; Richard Liu; Sima R. Patel; Andrew Watson; Guchen Yang; Anne Rose; Rodney Vickery; Janet Caceres-Cortes; Christian Caporuscio; Daniel M. Camac; Javed Khan; Yongmi An; William R. Foster; Paul Davies; John Hynes

High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.


Bioorganic & Medicinal Chemistry Letters | 2011

Pyrrolo[1,2-f]triazines as JAK2 inhibitors: Achieving potency and selectivity for JAK2 over JAK3.

Lalgudi S. Harikrishnan; Muthoni G. Kamau; Honghe Wan; Jennifer Inghrim; Kurt Zimmermann; Xiaopeng Sang; Harold Mastalerz; Walter Lewis Johnson; Guifen Zhang; Louis J. Lombardo; Michael A. Poss; George L. Trainor; John S. Tokarski; Matthew V. Lorenzi; Dan You; Marco M. Gottardis; Kathy F. Baldwin; Jonathan Lippy; David S. Nirschl; Ruhui Qiu; Arthur V. Miller; Javed Khan; John S. Sack; Ashok V. Purandare

SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.


ACS Medicinal Chemistry Letters | 2015

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

Honghe Wan; Gretchen M. Schroeder; Amy C. Hart; Jennifer Inghrim; James W. Grebinski; John S. Tokarski; Matthew V. Lorenzi; Dan You; Theresa McDevitt; Becky Penhallow; Ragini Vuppugalla; Yueping Zhang; Xiaomei Gu; Ramaswamy Iyer; Louis J. Lombardo; George L. Trainor; Stefan Ruepp; Jonathan Lippy; Yuval Blat; John S. Sack; Javed Khan; Kevin Stefanski; Bogdan Sleczka; Arvind Mathur; Jung-Hui Sun; Michael K. Wong; Dauh-Rurng Wu; Peng Li; Anuradha Gupta; Piramanayagam Arunachalam

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.


Bioorganic & Medicinal Chemistry Letters | 2014

Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors.

James J.-W. Duan; Zhonghui Lu; Bin Jiang; Bingwei V. Yang; Lidia M. Doweyko; David S. Nirschl; Lauren Haque; Shuqun Lin; Gregory D. Brown; John Hynes; John S. Tokarski; John S. Sack; Javed Khan; Jonathan Lippy; Rosemary Zhang; Sidney Pitt; Guoxiang Shen; William J. Pitts; Percy H. Carter; Joel C. Barrish; Steven G. Nadler; Luisa Salter-Cid; Murray McKinnon; Aberra Fura; Gary L. Schieven; Stephen T. Wrobleski

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.


Bioorganic & Medicinal Chemistry Letters | 2013

The discovery of BMS-457, a potent and selective CCR1 antagonist

Daniel S. Gardner; Joseph B. Santella; John V. Duncia; Percy H. Carter; T. G. Murali Dhar; Hong Wu; Weiwei Guo; Cullen L. Cavallaro; Katy Van Kirk; Melissa Yarde; Stephanie W. Briceno; R. Robert Grafstrom; Richard Liu; Sima R. Patel; Andrew J. Tebben; Dan Camac; Javed Khan; Andrew Watson; Guchen Yang; Anne Rose; William R. Foster; Mary Ellen Cvijic; Paul Davies; John Hynes

A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.


Bioorganic & Medicinal Chemistry Letters | 2015

9H-Carbazole-1-carboxamides as potent and selective JAK2 inhibitors

Kurt Zimmermann; Xiaopeng Sang; Harold Mastalerz; Walter Lewis Johnson; Guifen Zhang; Qingjie Liu; Douglas G. Batt; Louis J. Lombardo; Dinesh Vyas; George L. Trainor; John S. Tokarski; Matthew V. Lorenzi; Dan You; Marco M. Gottardis; Jonathan Lippy; Javed Khan; John S. Sack; Ashok V. Purandare

The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.


ACS Medicinal Chemistry Letters | 2015

Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.

Amy C. Hart; Gretchen M. Schroeder; Honghe Wan; James W. Grebinski; Jennifer Inghrim; James Kempson; Junqing Guo; William J. Pitts; John S. Tokarski; John S. Sack; Javed Khan; Jonathan Lippy; Matthew V. Lorenzi; Dan You; Theresa McDevitt; Ragini Vuppugalla; Yueping Zhang; Louis J. Lombardo; George L. Trainor; Ashok V. Purandare

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.


Bioorganic & Medicinal Chemistry Letters | 2018

Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity

Hua Gong; David S. Weinstein; Zhonghui Lu; James J.-W. Duan; Sylwia Stachura; Lauren Haque; Ananta Karmakar; Hemalatha Hemagiri; Dhanya Kumar Raut; Arun Kumar Gupta; Javed Khan; Dan Camac; John S. Sack; Andrew T. Pudzianowski; Dauh-Rurng Wu; Melissa Yarde; Ding-Ren Shen; Virna Borowski; Jenny Xie; Huadong Sun; Celia D'Arienzo; Marta Dabros; Michael A. Galella; Faye Wang; Carolyn A. Weigelt; Qihong Zhao; William R. Foster; John E. Somerville; Luisa Salter-Cid; Joel C. Barrish

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


Bioorganic & Medicinal Chemistry Letters | 2017

Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors

John Hynes; Hong Wu; James Kempson; James J.-W. Duan; Zhonghui Lu; Bin Jiang; Sylwia Stachura; John S. Tokarski; John S. Sack; Javed Khan; Jonathan Lippy; Rosemary Zhang; Sidney Pitt; Guoxiang Shen; Kate Gillooly; Kim W. McIntyre; Percy H. Carter; Joel C. Barrish; Steven G. Nadler; Luisa Salter-Cid; Aberra Fura; Gary L. Schieven; William J. Pitts; Stephen T. Wrobleski

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

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Dan You

Bristol-Myers Squibb

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Hong Wu

Bristol-Myers Squibb

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