Nicholas R. Wurtz
Bristol-Myers Squibb
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Publication
Featured researches published by Nicholas R. Wurtz.
Journal of Medicinal Chemistry | 2015
Daniel L. Cheney; Jeffrey M. Bozarth; William J. Metzler; Paul E. Morin; Luciano Mueller; John A. Newitt; Alexandra H. Nirschl; Alan R. Rendina; James Tamura; Anzhi Wei; Xiao Wen; Nicholas R. Wurtz; Dietmar A. Seiffert; Ruth R. Wexler; E. Scott Priestley
A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.
ACS Medicinal Chemistry Letters | 2014
Xiaojun Zhang; Wen Jiang; S. Jacutin-Porte; P.W. Glunz; Y. Zou; X. Cheng; A.H. Nirschl; Nicholas R. Wurtz; Joseph M. Luettgen; Alan R. Rendina; G. Luo; Timothy M. Harper; Anzhi Wei; R. Anumula; Daniel L. Cheney; R.M. Knabb; Pancras C. Wong; Ruth R. Wexler; E.S. Priestley
Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t 1/2 in dog PK studies.
Journal of Medicinal Chemistry | 2016
Peter W. Glunz; Luciano Mueller; Daniel L. Cheney; Vladimir Ladziata; Yan Zou; Nicholas R. Wurtz; Anzhi Wei; Pancras C. Wong; Ruth R. Wexler; E. Scott Priestley
Incorporation of a methyl group onto a macrocyclic FVIIa inhibitor improves potency 10-fold but is accompanied by atropisomerism due to restricted bond rotation in the macrocyclic structure, as demonstrated by NMR studies. We designed a conformational constraint favoring the desired atropisomer in which this methyl group interacts with the S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint was prepared and demonstrated by NMR to reside predominantly in the desired conformation. This modification improved potency 180-fold relative to the unsubstituted, racemic macrocycle and improved selectivity. An X-ray crystal structure of a closely related analogue in the FVIIa active site was obtained and matches the NMR and modeled conformations, confirming that this conformational constraint does indeed direct the methyl group into the S2 pocket as designed. The resulting rationally designed, conformationally stable template enables further optimization of these macrocyclic inhibitors.
Bioorganic & Medicinal Chemistry Letters | 2017
Xiaojun Zhang; Peter W. Glunz; Eldon Scott Priestley; James A. Johnson; Nicholas R. Wurtz; Vladimir Ladziata
A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.
Bioorganic & Medicinal Chemistry Letters | 2017
Nicholas R. Wurtz; Brandon Parkhurst; Indawati Delucca; Peter W. Glunz; Wen Jiang; Xiaojun Zhang; Daniel L. Cheney; Jeffrey M. Bozarth; Alan R. Rendina; Anzhi Wei; Tim Harper; Joseph M. Luettgen; Yiming Wu; Pancras C. Wong; Dietmar Seiffert; Ruth R. Wexler; E. Scott Priestley
Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.
Archive | 2007
Eldon Scott Priestley; Daniel L. Cheney; Nicholas R. Wurtz; Peter W. Glunz
Archive | 2005
Peter W. Glunz; Nicholas R. Wurtz; Xuhong Cheng
Journal of Medicinal Chemistry | 2016
Xiaojun Zhang; Peter W. Glunz; James A. Johnson; Wen Jiang; Swanee Jacutin-Porte; Vladimir Ladziata; Yan Zou; Monique Phillips; Nicholas R. Wurtz; Brandon Parkhurst; Alan R. Rendina; Timothy M. Harper; Daniel L. Cheney; Joseph M. Luettgen; Pancras C. Wong; Dietmar A. Seiffert; Ruth R. Wexler; E. Scott Priestley
Archive | 2007
Nicholas R. Wurtz; Eldon Scott Priestley; Daniel L. Cheney; Xiaojun Zhang; Brandon Parkhurst; Vladimir Ladziata
Archive | 2016
Andrew Quoc Viet; Nicholas R. Wurtz