De Novo Fragment Design: A Medicinal Chemistry Approach to Fragment-Based Lead Generation

Talamás, Francisco X.; Ao-Ieong, Gloria; Brameld, Ken A.; Chin, Elbert; Vicente, Javier de; Dunn, James P.; Ghate, M.; Giannetti, Anthony M.; Harris, S.F.; Labadie, Sharada S.; Lévêque, Vincent; Li, Jim; Lui, Alfred S.; McCaleb, Kristen L.; Nájera, Isabel; Schoenfeld, Ryan C.; Wang, Beihan; Wong, Allen

doi:10.1021/jm4002605

Cited by 32 publications

(29 citation statements)

References 17 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of these multiple, complementary methods could increase the success rate of identifying new SIRT5 inhibitors. In addition to above described methods, structure-based or pharmacophore-based de novo design methods (Schneider and Fechner, 2005;Talamas et al, 2013) as well as scaffold hopping or substitute modification methods (Li et al, 2015b;Mauser and Guba, 2008) are worth to use because these methods might be able to discover novel SIRT5 inhibitors with novel chemical scaffolds.…”

Section: Clues and Methods For The Design Of New Sirt5 Inhibitorsmentioning

confidence: 99%

Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors

Yang

et al. 2016

Sci. China Life Sci.

View full text Add to dashboard Cite

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylases, which regulate important biological processes ranging from apoptosis, age-associated pathophysiologies, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. Very recently, sirtuin 5 (SIRT5) has received considerable attention due to that it was found to have weak deacetylase activity but strong desuccinylase, demalonylase and deglutarylase activities, and it was also found to be associated with several human diseases such as cancer, Alzheimer's disease, and Parkinson's disease. In this review, we for the first time summarized the structure characteristics, known peptide and small-molecule inhibitors of SIRT5, extracted some clues from current available information and introduced some feasible, practical in silico methods, which might be useful in further efforts to develop new SIRT5 inhibitors.Sirtuin, SIRT5 inhibitor, crystal structure, small-molecule inhibitors, computer-aided drug design Citation:Yang, L., Ma, X., He, Y., Yuan, C., Chen, Q., Li, G., and Chen, X. (2017). Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors. Sci China Life Sci 60, 249-256.

show abstract

Section: Clues and Methods For The Design Of New Sirt5 Inhibitorsmentioning

confidence: 99%

Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors

Yang

et al. 2016

Sci. China Life Sci.

View full text Add to dashboard Cite

show abstract

“…More recently, we reported the pioneering use of de novo fragment design that enabled us to generate a novel, low molecular weight (MW) lead structure (compound 2 , Figure 2). 26 Pyridone 2 exhibits potent inhibition of NS5B enzymatic activity (Table 1), especially considering its small size. Given the low MW and high ligand efficiency (LE = 0.46), we felt 2 was a reasonable starting place from which to develop potent inhibitors of NS5B that would also possess desirable physicochemical and ADMET properties required for a safe, orally delivered drug candidate.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B

et al. 2013

Self Cite

View full text Add to dashboard Cite

Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Towards those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition which has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.

show abstract

“…These interactions are the same as those observed previously with the original fragment 6 . 15 The nitrogen of the quinoline core is within bonding distance to a conserved molecule of water (not shown on Figure 3). The main role for this ring, as replacement of the vinyl group, is to hold the linker of the methanesulfonamide in the right position.…”

Section: Resultsmentioning

confidence: 99%

“…The development of fragment 6 to a compound that was selected for clinical development is another successful case where the use of fragments 15 together with structure-based design 16 led to the selection of a clinical candidate.…”

Section: Resultsmentioning

confidence: 99%

Discovery of N-[4-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a Potent Inhibitor of the Hepatitis C Virus NS5B Polymerase

et al. 2013

Self Cite

View full text Add to dashboard Cite

In the last few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAA). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. Continuing our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic head groups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109) which was selected for advancement to clinical development.

show abstract

De Novo Fragment Design: A Medicinal Chemistry Approach to Fragment-Based Lead Generation

Cited by 32 publications

References 17 publications

Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors

Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors

Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B

Discovery of N-[4-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a Potent Inhibitor of the Hepatitis C Virus NS5B Polymerase

Contact Info

Product

Resources

About