Publications by authors named "Jianwei Bian"

20 Publications

  • Page 1 of 1

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

J Med Chem 2021 05 30;64(9):6329-6357. Epub 2021 Apr 30.

Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound , which has potent activity against Gram-positive bacteria, a favorable safety profile, and excellent pharmacokinetic properties. Compound was found to be efficacious against fluoroquinolone-sensitive infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from , compound , and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of compared to fluoroquinolones.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00375DOI Listing
May 2021

[A Preliminary Study to Evaluate the Efficacy and Safety of A Optimized Computed Tomography-guided Pulmonary Nodule Microcoil Localization Technique].

Zhongguo Fei Ai Za Zhi 2019 Jun;22(6):349-354

Department of Thoracic Surgery, Beijing Aerospace General Hospital, Beijing 100076, China.

Background: Preoperative computed tomography (CT) guided microcoil localization is a common method for small lung nodules before video-assisted thoracoscopic surgery (VATS). However, this method still has some limitation such as complicated operation and slight complications. We have optimized the original method. The purpose of this study was to investigate the clinical value of this optimized method.

Methods: 35 pulmonary nodules from 31 patients between September 2018 and January 2019 were localized by the optimized method before VATS. The success rate, complications, pathological results and localization operations related data were statistically analyzed.

Results: The success rate of localization was 97.1%, and the success rate of VATS removal was 100%. The average operation time was 10.1 min (5 min-31 min), and the average time required for resection of lesions was 38.2 min (10 min-100 min). During the surgery, the microcoil of one patient was found to be dislocated and retracted into the chest wall. A puncture needle was inserted intolung tissue from the chest wall puncture point after the lung was inflated, and then the pulmonary nodule were successfully located and removed. A minor pneumothorax occurred in 3 patients, but no closed drainage was needed. Three patients developed intrapulmonary hematoma. The pathological results of 35 pulmonary nodules included 15 well-differentiated adenocarcinoma, 7 carcinoma in situ, 5 microinvasive adenocarcinoma, 4 atypical adenomatoid hyperplasia, 2 intrapulmonary lymph node hyperplasia, 2 inflammatory nodules.

Conclusions: For small pulmonary nodules requiring thoracoscopic surgery, the optimized computed tomography-guided pulmonary nodule microcoil localization technique is convenient, safe and effective, and worthy of promotion to use.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2019.06.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580085PMC
June 2019

[Preoperative Computed Tomography-guided Microcoil Localization for Multiple Small Lung Nodules before Video-assisted Thoracoscopic Surgery].

Zhongguo Fei Ai Za Zhi 2018 Nov;21(11):857-863

Department of Thoracic Surgery, Beijing Aerospace General Hospital, Beijing 100076, China.

Background: Localization of multiple small lung nodules is the technical difficulty of minimally invasive operation resection. However, there are few clinical studies on the preoperative localization of multiple small lung nodules. This study was designed to evaluate the clinical value of preoperative computed tomography (CT) guided microcoil localization for multiple small lung nodules compared with single small lung nodule before video-assisted thoracoscopic surgery (VATS).

Methods: A retrospective analysis of the clinical data of 235 patients with preoperative pulmonary nodules microcoil localization was performed. According to whether the nodules were single, they were divided into single nodule group (184 cases) and multiple nodules group (51 cases) (multiple nodules group). The single nodule group was positioned under CT-guided conventional methods. The multiple nodules group were CT guided localized by microcoil in batches according to priority before VATS. The success rate, complications, pathological results and localization operations related data were statistically analyzed.

Results: The success rate of localization in multiple nodule groups was 90.2%, there was no significant difference compared with the single nodule group (90.2% vs 94.6%, P=0.205). The occurrence rate of pneumothorax in multiple nodule group and single nodule group was no statistical difference (21.6% vs 14.1%, P=0.179), however, the operation time in the multiple nodule group was significantly longer than the single nodule group [(30.6±6.6) min vs (19.9±7.4) min, P=0.000]. There were no serious complications such as massive hemoptysis, air embolism or hemothorax. There was no conversion to thoracotomy due to failure of localizing the nodules during operation. Sub-lobectomy was the main method of operation. The majority of postoperative pathologies were non-invasive carcinomas.

Conclusions: For multiple small lung pulmonary nodules requiring thoracoscopic surgery, according to certain strategies, preoperative CT-guided localized by microcoil in batches according to priority before VATS is safe and effective, and worthy of promotion.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2018.11.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247003PMC
November 2018

Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.

J Med Chem 2018 08 27;61(15):6779-6800. Epub 2018 Jul 27.

Pfizer Worldwide R&D, Groton Laboratories , Eastern Point Road , Groton , Connecticut 06340 , United States.

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00633DOI Listing
August 2018

Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2).

J Med Chem 2015 Sep;58(18):7173-85

Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01006DOI Listing
September 2015

Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry.

J Org Chem 2015 Jul 24;80(14):7266-74. Epub 2015 Jun 24.

Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within α,β-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible.
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http://dx.doi.org/10.1021/acs.joc.5b00853DOI Listing
July 2015

Identification of a novel conformationally constrained glucagon receptor antagonist.

Bioorg Med Chem Lett 2014 Feb 28;24(3):839-44. Epub 2013 Dec 28.

Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.

Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.
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http://dx.doi.org/10.1016/j.bmcl.2013.12.090DOI Listing
February 2014

Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif.

Bioorg Med Chem Lett 2013 Aug 20;23(16):4571-8. Epub 2013 Jun 20.

Cardiovascular, Metabolic, and Endocrine Diseases Chemistry, Pfizer Worldwide Research and Development, 620 Memorial Dr, Cambridge, MA 02139, USA.

Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
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http://dx.doi.org/10.1016/j.bmcl.2013.06.036DOI Listing
August 2013

The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus.

Bioorg Med Chem Lett 2013 May 13;23(10):3051-8. Epub 2013 Mar 13.

Pfizer Wordwide Research and Development, Eastern Point Road, Groton, CT 06442, USA.

A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.
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http://dx.doi.org/10.1016/j.bmcl.2013.03.014DOI Listing
May 2013

Diastereoselective synthesis of β-heteroaryl syn-α-methyl-β-amino acid derivatives via a double chiral auxiliary approach.

Org Lett 2013 Feb 23;15(3):562-5. Epub 2013 Jan 23.

Neusentis Chemistry, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA.

The addition of the SuperQuat enolate to five- and six-membered heterocyclic tert-butyl sulfinimines led to a high syn-selectivity of up to 99:1 in good to excellent yields. The reaction is tentatively proposed to proceed through an open-chain transition state with the presence of an α-heteroatom on the sulfinimine leading to high diastereoselectivities. The adducts were derivatized to β-amino esters and amides in a facile manner.
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http://dx.doi.org/10.1021/ol3033785DOI Listing
February 2013

The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of type 2 diabetes mellitus.

Bioorg Med Chem Lett 2012 Dec 29;22(23):7100-5. Epub 2012 Sep 29.

Pfizer Cardiovascular, Metabolic and Endocrine Disease Research Unit, Pfizer Worldwide Research and Development, 620 Memorial Drive, Cambridge, MA 02139, USA.

Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.
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http://dx.doi.org/10.1016/j.bmcl.2012.09.082DOI Listing
December 2012

Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus.

J Med Chem 2012 Feb 24;55(3):1318-33. Epub 2012 Jan 24.

Cambridge Laboratories, Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.
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http://dx.doi.org/10.1021/jm2014887DOI Listing
February 2012

A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicity.

Bioorg Med Chem Lett 2012 Jan 6;22(1):415-20. Epub 2011 Nov 6.

Pfizer Worldwide Research & Development, Eastern Point Rd, Groton, CT 06442, USA.

A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.
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http://dx.doi.org/10.1016/j.bmcl.2011.10.113DOI Listing
January 2012

Enantioselective total synthesis of (-)-kibdelone C.

J Am Chem Soc 2011 Jul 15;133(26):9956-9. Epub 2011 Jun 15.

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, USA.

The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton.
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http://dx.doi.org/10.1021/ja204040kDOI Listing
July 2011

Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors.

J Med Chem 2011 Apr 30;54(8):2952-60. Epub 2011 Mar 30.

Groton Laboratories, Pfizer Global Research & Development, Groton, Connecticut 06340, United States.

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1021/jm200049rDOI Listing
April 2011

Functionalization of aromatic amino acids via direct C-H activation: generation of versatile building blocks for accessing novel peptide space.

Org Lett 2010 Sep;12(17):3870-3

Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Functionalized alpha-amino acid building blocks have been prepared in good yield with high regiocontrol and preservation of stereochemistry via iridium-catalyzed borylation of suitably protected aromatic alpha-amino acid derivatives. The utility of these systems in peptide couplings and Suzuki reactions has been demonstrated.
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http://dx.doi.org/10.1021/ol1015674DOI Listing
September 2010

Enantioselective total synthesis of (+)- and (-)-nigellamine A2.

J Am Chem Soc 2006 Jun;128(23):7428-9

Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Texas 75390-9038, USA.

The nigellamine alkaloids are dolabellane diterpenes displaying potent lipid metabolism-promoting activity. Total synthesis of (+)- and (-)-nigellamine A2 has been accomplished. Absolute stereochemistry of synthetic nigellamine A2 was established through an intramolecular asymmetric allylic alkylation using a Pd(phosphinooxazoline) catalyst. Other notable transformations include a radical alkynylation, a diastereoselective Nozaki-Hiyama-Kishi cyclization, and a regio- and stereoselective catalytic epoxidation. On the basis of X-ray crystallographic analysis of an optically active intermediate, we have confirmed the assigned absolute stereochemistry of the natural product. Minor modifications of the synthetic sequence outlined here should provide access to the other nigellamine alkaloids.
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http://dx.doi.org/10.1021/ja061559nDOI Listing
June 2006

Vesicular latex.

Angew Chem Int Ed Engl 2004 Feb;43(10):1265-7

Department of Chemistry, Emory University, Atlanta, GA 3O322, USA.

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http://dx.doi.org/10.1002/anie.200352936DOI Listing
February 2004

Bolaforms with fourteen galactose units: a proposed site-directed cohesion of cancer cells.

Org Lett 2004 Jan;6(2):261-4

Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.

[structure: see text] The multistep synthesis of a calixarene joined to a second calixarene via a long spacer is described. Since each calixarene bears multiple galactose-based units (known to bind strongly to rat hepatoma cells), there existed the possibility of cross-linking the cancer cells into a network. The compounds did not serve this purpose, a fact potentially correctable by adjusting or rigidifying the spacer. Formation of a "cancer net" around a solid tumor remains a viable approach to retarding growth and/or inhibiting metastasis.
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http://dx.doi.org/10.1021/ol030135kDOI Listing
January 2004

A 1,3,5-triaxial triaminocyclohexane: the triamine corresponding to Kemp's triacid.

Angew Chem Int Ed Engl 2002 Jul;41(14):2581-4

Department of Chemistry, Emory University, Atlanta, GA 30322, USA.

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http://dx.doi.org/10.1002/1521-3773(20020715)41:14<2581::AID-ANIE2581>3.0.CO;2-#DOI Listing
July 2002