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Dive into the research topics where Robert Aslanian is active.

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Featured researches published by Robert Aslanian.


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.


European Journal of Pharmacology | 2010

Pharmacology of a potent and selective inhibitor of PDE4 for inhaled administration.

Richard W. Chapman; Aileen House; Jennifer Richard; Dan Prelusky; James Lamca; Peng Wang; Dan Lundell; Ping Wu; Pauline C. Ting; Joe F. Lee; Robert Aslanian; Jonathan Phillips

A strategy to overcome the side effect liabilities of oral PDE4 inhibitors has been to deliver the drugs by inhalation. In this report, we identify 1-[[5-(1(S)-aminoethly)-2-[8-methoxy-2-(triflurormethyl)-5-quinolinyl]-4-oxazolyl] carbonyl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester xinafoate salt, (COMPOUND 1) as a potent and selective inhibitor of PDE4 with biological and pharmacokinetic properties suitable for delivery by the inhaled route. COMPOUND 1 potently inhibits human PDE4 (IC(50)=70pM) with little or no activity against other PDEs. It is highly potent against PDE4B and PDE4D which are important isoforms of PDE4 controlling inflammation and airway functions. In an allergen-challenged Brown Norway rat model of asthma, COMPOUND 1 inhibited the late phase influx of inflammatory cells and reductions in lung function following its administration by the intratracheal or nose-only routes of administration. Important differences were seen between intratracheal COMPOUND 1 and our previously published results with the oral PDE4 inhibitor roflumilast (Celly et al., 2005), as COMPOUND 1 rapidly (within 1h) reversed the decline in lung function when it was given therapeutically to rats already challenged with antigen. COMPOUND 1 was weakly active by the oral route which is a finding consistent with results showing this compound has poor oral bioavailability in animals. Positive interactions between COMPOUND 1 and albuterol, and COMPOUND 1 and mometasone furoate were seen on the improvement in lung functions in allergen-challenged rats. These results identify COMPOUND 1 as a potent and selective inhibitor of PDE4 with properties suitable for delivery by inhalation.


Bioorganic & Medicinal Chemistry Letters | 2012

Facile synthesis of tetracyclic azepine and oxazocine derivatives and their potential as MAPKAP-K2 (MK2) inhibitors.

Ashwin U. Rao; Dong Xiao; Xianhai Huang; Wei Zhou; James Fossetta; Dan Lundell; Fang Tian; Prashant Trivedi; Robert Aslanian; Anandan Palani

Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.


Bioorganic & Medicinal Chemistry Letters | 2011

Discovery of fused 5,6-bicyclic heterocycles as γ-secretase modulators

Jun Qin; Pawan Dhondi; Xianhai Huang; Mihirbaran Mandal; Zhiqiang Zhao; Dmitri Pissarnitski; Wei Zhou; Robert Aslanian; Zhaoning Zhu; William J. Greenlee; John W. Clader; Lili Zhang; Mary Cohen-Williams; Nicholas Jones; Lynn Hyde; Anandan Palani

We herein report the discovery of four series of fused 5,6-bicyclic heterocycles as γ-secretase modulators. Synthesis and SAR of these series are discussed. These compounds represent a new class of γ-secretase modulators that demonstrate moderate to good in vitro potency in inhibiting Aβ(42) production.


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 | 2013

The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer’s disease

Hongmei Li; Jun Qin; Pawan Dhondi; Wei Zhou; Monica Vicarel; Thomas Bara; David Cole; Hubert Josien; Dmitri Pissarnitski; Zhaoning Zhu; Anandan Palani; Robert Aslanian; John W. Clader; Michael Czarniecki; William J. Greenlee; Mary Cohen-Williams; Lynn Hyde; Lixin Song; Lili Zhang; Inhou Chu; Xianhai Huang

In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimers disease.


Bioorganic & Medicinal Chemistry Letters | 2012

A three-step protocol for lead optimization: Quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors

Xianhai Huang; Xiaohong Zhu; Xiao Chen; Wei Zhou; Dong Xiao; Sylvia Degrado; Robert Aslanian; James Fossetta; Daniel Lundell; Fang Tian; Prashant Trivedi; Anandan Palani

A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.


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

Discovery of a series of potent arylthiadiazole H3 antagonists

Dong Xiao; Anandan Palani; Michael Sofolarides; Ying Huang; Robert Aslanian; Henry M. Vaccaro; Liwu Hong; Brian A. McKittrick; Robert E. West; Shirley M. Williams; Ren-Long Wu; Joyce Hwa; Christopher Sondey; Jean Lachowicz

A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.


Bioorganic & Medicinal Chemistry Letters | 2013

Conformation constraint of anilides enabling the discovery of tricyclic lactams as potent MK2 non-ATP competitive inhibitors.

Dong Xiao; Anandan Palani; Xianhai Huang; Michael Sofolarides; Wei Zhou; Xiao Chen; Robert Aslanian; Zhuyan Guo; James Fossetta; Fang Tian; Prashant Trivedi; Peter Spacciapoli; Charles Whitehurst; Daniel Lundell

Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.

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