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Lai Z.-W.,CAS Shanghai Institute of Organic Chemistry | Lai Z.-W.,China Pharmaceutical University | Yang R.-F.,Pharmaron Beijing Ltd. Co. | Ye K.-Y.,CAS Shanghai Institute of Organic Chemistry | And 2 more authors.
Beilstein Journal of Organic Chemistry | Year: 2014

A class of novel, easily accessible and air-stable 1-[bis(trifluoromethyl) phosphine]-1'-oxazolinylferrocene ligands has been synthesized from ferrocene. It became apparent that these ligands can be used in the regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates in a highly efficient manner. Excellent regio- and enantioselectivity could be obtained for a wide range of substrates. © 2014 Lai et al; licensee Beilstein-Institut.


Harriman G.,Nimbus Therapeutics | Greenwood J.,Schrodinger | Bhat S.,Schrodinger | Huang X.,Pharmaron Beijing Ltd. Co. | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2016

Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.


Zheng X.,FORMA Therapeutics | Bauer P.,FORMA Therapeutics | Baumeister T.,FORMA Therapeutics | Buckmelter A.J.,FORMA Therapeutics | And 18 more authors.
Journal of Medicinal Chemistry | Year: 2013

Nicotinamide phosphoribosyltransferase (Nampt) is a promising anticancer target. Virtual screening identified a thiourea analogue, compound 5, as a novel highly potent Nampt inhibitor. Guided by the cocrystal structure of 5, SAR exploration revealed that the corresponding urea compound 7 exhibited similar potency with an improved solubility profile. These studies also indicated that a 3-pyridyl group was the preferred substituent at one inhibitor terminus and also identified a urea moiety as the optimal linker to the remainder of the inhibitor structure. Further SAR optimization of the other inhibitor terminus ultimately yielded compound 50 as a urea-containing Nampt inhibitor which exhibited excellent biochemical and cellular potency (enzyme IC50 = 0.007 μM; A2780 IC50 = 0.032 μM). Compound 50 also showed excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model (TGI of 97% was observed on day 17). © 2013 American Chemical Society.


Zheng X.,FORMA Therapeutics | Bauer P.,FORMA Therapeutics | Baumeister T.,FORMA Therapeutics | Buckmelter A.J.,FORMA Therapeutics | And 23 more authors.
Journal of Medicinal Chemistry | Year: 2013

Crystal structures of several urea- and thiourea-derived compounds in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein were utilized to design a potent amide-containing inhibitor bearing an aza-indole moiety (7, Nampt BC IC50 = 9.0 nM, A2780 cell proliferation IC 50 = 10 nM). The Nampt-7 cocrystal structure was subsequently obtained and enabled the design of additional amide-containing inhibitors which incorporated various other fused 6,5-heterocyclic moieties and biaryl sulfone or sulfonamide motifs. Additional modifications of these molecules afforded many potent biaryl sulfone-containing Nampt inhibitors which also exhibited favorable in vitro ADME properties (microsomal and hepatocyte stability, MDCK permeability, plasma protein binding). An optimized compound (58) was a potent inhibitor of multiple cancer cell lines (IC50 <10 nM vs U251, HT1080, PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties (F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a U251 mouse xenograft model. © 2013 American Chemical Society.


Shi Y.-C.,CAS Shanghai Institute of Organic Chemistry | Yang R.-F.,CAS Shanghai Institute of Organic Chemistry | Yang R.-F.,Pharmaron Beijing Ltd. Co. | Gao D.-W.,CAS Shanghai Institute of Organic Chemistry | You S.-L.,CAS Shanghai Institute of Organic Chemistry
Beilstein Journal of Organic Chemistry | Year: 2013

When Boc-L-Val-OH was used as a ligand for the enantioselective Pd(II)-catalyzed annulation of N,N-substituted aminomethyl ferrocene derivatives with diarylethynes, ferrocenes with planar chirality could be achieved with excellent enantioselectivity (up to 99% ee). © 2013 Shi et al.

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