Publications by authors named "Jimmy Liang"

6 Publications

  • Page 1 of 1

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

J Med Chem 2017 06 25;60(11):4559-4572. Epub 2017 May 25.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.7b00408DOI Listing
June 2017

Allyl-Assisted, Cu(I)-Catalyzed Azide-Alkyne Cycloaddition/Allylation Reaction: Assembly of the [1,2,3]Triazolo-4,5,6,7-tetrahydropyridine Core Structure.

J Org Chem 2015 Nov 20;80(21):11003-12. Epub 2015 Oct 20.

Janssen Research & Development LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

We report a Cu(I)-catalyzed azide-alkyne-allyl halide three-component reaction for a one-pot synthesis of 1,4-disubstituted 5-allyl-1,2,3-triazoles. The allyl moiety provides not only the electrophile but also a coordinating ligand to Cu, which is essential for the reaction to occur under mild conditions. A concise synthesis of a potential drug candidate 1 is realized based on this key reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.5b02174DOI Listing
November 2015

Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.

Bioorg Med Chem Lett 2013 Feb 5;23(3):811-5. Epub 2012 Dec 5.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2012.11.074DOI Listing
February 2013

Practical synthesis of a Cathepsin S inhibitor: route identification, purification strategies, and serendipitous discovery of a crystalline salt form.

J Org Chem 2010 Mar;75(6):1940-7

Johnson & Johnson Pharmaceutical Research & Development LLC, 3210 Merryfield Row, San Diego, California 92121, USA.

A "redox economical" strategy resulted in a concise, modular synthesis of compound 1, a potent Cathepsin S inhibitor. Starting from three building blocks, crude drug substance was prepared in a two-step sequence in high yield. Efficient purification of the crude drug substance was accomplished via the formation of an unusual monoethyl oxalate salt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo902650bDOI Listing
March 2010

Design of concise, scalable route to a cholecystokinin 1 (CCK 1) receptor antagonist.

J Org Chem 2007 Oct 22;72(22):8243-50. Epub 2007 Sep 22.

Department of Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Development of efficient, scalable routes for the synthesis of (S)-3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl propionic acid, a selective cholecystokinin 1 (CCK 1) receptor antagonist, is described. A key feature of the scale-up route is a concise construction of the complete pyrazole framework in a single step by reacting an aryl hydrazine with an elaborated acetylenic ketone. This route was then further refined incorporating efficient enantioselective strategies to obtain the desired S-enantiomer in high optical purity. The first strategy involved an efficient, recyclable, kinetic resolution by enzyme-catalyzed hydrolysis of the racemic ester. In the second-generation route, the requisite stereochemistry at the chiral center was generated at an early stage in the synthesis involving a remarkable diastereoselective addition of inexpensive (S)-(-)-ethyl lactate to an alkylaryl ketene. Both methods furnished optically pure (>99% ee) final drug substance as its crystalline sodium salt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo071166mDOI Listing
October 2007

Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist.

Bioorg Med Chem 2002 Jun;10(6):2051-66

Department of Chemical Science, Tanabe Research Laboratories, USA, Inc., 4540 Towne Centre Court, San Diego, CA 92121, USA.

alpha(4)beta(1) and alpha(4)beta(7) integrins are key regulators of physiologic and pathologic responses in inflammation and autoimmune disease. The effectiveness of anti-integrin antibodies to attenuate a number of inflammatory/immune conditions provides a strong rationale to target integrins for drug development. Important advances have been made in identifying potent and selective candidates, peptides and peptidomimetics, for further development. Herein, we report the discovery of a series of novel N-benzoyl-L-biphenylalanine derivatives that are potent inhibitors of alpha4 integrins. The potency of the initial lead compound (1: IC(50) alpha(4)beta(7)/alpha(4)beta(1)=5/33 microM) was optimized via sequential manipulation of substituents to generate low nM, orally bioavailable dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. The SAR also led to the identification of several subnanomolar antagonists (134, 142, and 143). Compound 81 (TR-14035; IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe. The synthesis, SAR and biological evaluation of these compounds are described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0968-0896(02)00021-4DOI Listing
June 2002