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Featured researches published by Rongze Kuang.


Antimicrobial Agents and Chemotherapy | 2011

Discovery of a Novel Class of Orally Active Antifungal β-1,3-d-Glucan Synthase Inhibitors

Scott S. Walker; Yiming Xu; Ilias Triantafyllou; Michelle F. Waldman; Cara Mendrick; Nathaniel Brown; Paul A. Mann; Andrew S. Chau; Reena Patel; Nicholas Bauman; Christine Norris; Barry Antonacci; Maya Gurnani; Anthony Cacciapuoti; Paul M. McNicholas; Samuel Wainhaus; R. Jason Herr; Rongze Kuang; Robert Aslanian; Pauline C. Ting; Todd A. Black

ABSTRACT The echinocandins are a class of semisynthetic natural products that target β-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.


Bioorganic & Medicinal Chemistry Letters | 2011

SAR studies of pyridazinone derivatives as novel glucan synthase inhibitors

Gang Zhou; Pauline C. Ting; Robert Aslanian; Jianhua Cao; David W. Kim; Rongze Kuang; Joe F. Lee; John Schwerdt; Heping Wu; R. Jason Herr; Andrew J. Zych; Jinhai Yang; Sang Lam; Samuel Wainhaus; Todd A. Black; Paul M. McNicholas; Yiming Xu; Scott S. Walker

A novel series of pyridazinone analogs has been developed as potent β-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.


Bioorganic & Medicinal Chemistry Letters | 2012

Discovery of oxazole-based PDE4 inhibitors with picomolar potency.

Rongze Kuang; Ho-Jane Shue; Li Xiao; David J. Blythin; Neng-Yang Shih; Xiao Chen; Danlin Gu; John Schwerdt; Ling Lin; Pauline C. Ting; Jianhua Cao; Robert Aslanian; John J. Piwinski; Daniel Prelusky; Ping Wu; Ji Zhang; Xiang Zhang; Chander S. Celly; Motasim Billah; Peng Wang

Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.


Bioorganic & Medicinal Chemistry Letters | 2011

The synthesis and structure-activity relationship of pyridazinones as glucan synthase inhibitors.

Pauline C. Ting; Rongze Kuang; Heping Wu; Robert Aslanian; Jianhua Cao; David W. Kim; Joe F. Lee; John Schwerdt; Gang Zhou; Samuel Wainhaus; Todd A. Black; Anthony Cacciapuoti; Paul M. McNicholas; Yiming Xu; Scott S. Walker

A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a β-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.


Bioorganic & Medicinal Chemistry Letters | 2016

Discovery of aminoquinazoline derivatives as human A2A adenosine receptor antagonists

Gang Zhou; Robert Aslanian; Gioconda V. Gallo; Tanweer Khan; Rongze Kuang; Biju Purakkattle; Manuel de Lera Ruiz; Andrew W. Stamford; Pauline Ting; Heping Wu; Hongwu Wang; Dong Xiao; Tao Yu; Yonglian Zhang; Deborra Mullins; Robert Hodgson

Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.


Bioorganic & Medicinal Chemistry Letters | 2013

Discovery of oral and inhaled PDE4 inhibitors.

Pauline C. Ting; Joe F. Lee; Rongze Kuang; Jianhua Cao; Danlin Gu; Ying Huang; Zhidan Liu; Robert Aslanian; Kung-I. Feng; Daniel Prelusky; James Lamca; Aileen House; Jonathan Phillips; Peng Wang; Ping Wu; Daniel Lundell; Richard W. Chapman; Chander S. Celly

The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.


Bioorganic & Medicinal Chemistry Letters | 2012

Lead optimization of a sulfonylurea-based piperazine pyridazinone series of glucan synthase inhibitors

Andrew J. Zych; Sang Q. Lam; David M. Jenkins; R. Jason Herr; Pauline C. Ting; Joe F. Lee; Rongze Kuang; Heping Wu; David W. Kim; Robert Aslanian; Samuel Wainhaus; Todd A. Black; Anthony Cacciapuoti; Paul M. McNicholas; Yiming Xu; Scott S. Walker

The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.


Bioorganic & Medicinal Chemistry Letters | 2012

The optimization of pyridazinone series of glucan synthase inhibitors

Rongze Kuang; Heping Wu; Pauline C. Ting; Robert Aslanian; Jianhua Cao; David W. Kim; Joe F. Lee; John Schwerdt; Gang Zhou; R. Jason Herr; Andrew J. Zych; Jinhai Yang; Sang Q. Lam; David M. Jenkins; Samuel A. Sakwa; Samuel Wainhaus; Todd A. Black; Anthony Cacciapuoti; Paul M. McNicholas; Yiming Xu; Scott S. Walker

A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.


Archive | 2009

BIARYL SPIROAMINOOXAZOLINE ANALOGUES AS ALPHA2C ADRENERGIC RECEPTOR MODULATORS

Kevin D. McCormick; Li Dong; Christopher W. Boyce; Lera Ruiz Manuel De; Salem Fevrier; Jie Wu; Junying Zheng; Younong Yu; Jianhua Chao; Walter Won; Ashwin U. Rao; Rongze Kuang; Pauline C. Ting; Xianhai Huang; Ning Shao; Anandan Palani; Michael Berlin; Robert Aslanian


Archive | 2014

PIPERAZINE-SUBSTITUTED 7-METHOXY-[1,2,4]TRIAZOLO[1,5-C]QUINAZOLIN-5-AMINE COMPOUNDS WITH A2A ANTAGONIST PROPERTIES

Amjad Ali; Michael Man-Chu Lo; Yeon-Hee Lim; Andrew Stamford; Rongze Kuang; Paul Tempest; Younong Yu; Michael Y. Berlin; Pauline Ting; Gang Zhou; Tao Yu; Christopher W. Boyce; Joseph M. Kelly; Jayaram R. Tagat; Junying Zheng; Xianhai Huang; Wei Zhou; Jae-Hun Kim; Nicolas Zorn; Dong Xiao; Gioconda V. Gallo; Walter Won; Heping Wu; Rajan Anand

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