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Resurrecting the Condemned: Identification of N‑Benzoxaborole Benzofuran GSK8175 as a Clinical Candidate with Reduced Metabolic Liability Peng Zhan,* Dongwei Kang, and Xinyong Liu*
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Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. China ABSTRACT: Recently, in a program designed to improve the metabolic stability of the HCV inhibitor GSK5852, Nbenzoxaborole benzofuran (GSK8175) emerged as a clinical candidate that not only retains the broad-spectrum activity against HCV subgenomic replicons but is free of the Nbenzylboronic acid structure, which is a metabolic liability, and probably the cause of low in vivo clearance in preclinical species. This Viewpoint discusses some medicinal chemistry issues involved in the identification of GSK8175.
1. INTRODUCTION Hepatitis C virus (HCV) NS5B is a RNA-dependent-RNA polymerase that catalyzes the synthesis of progenic viral RNA strands and, due to its apparent sequence and structural differences with human DNA and RNA polymerases, represents an attractive target for the development of HCV selective inhibitors.1 In 2010, GSK5852 (1), a NS5B inhibitor, was selected as a candidate for clinical development for the treatment of HCV infection. The benzylboronic acid in 1 is a critical pharmacophore for the broad spectrum antiviral activity against HCV genotype (GT) 1−6 replicons, as well as clinically relevant resistant strains, because the activity of 1 could not be replicated with conventional acid isosteres.2 However, its plasma half-life of 5 h is low. Its facile benzylic oxidation and formation in vivo of 2 and 4-borono-3fluorobenzoic acid (3) have been found to be the reason for the poor half-life. A plausible mechanism for the formation of 3 involves facile oxidation of the benzylic carbon and subsequent C−N bond cleavage (Figure 1). On the basis of the hypothesis that reduction or elimination of the benzylic oxidation associated with benzyl boronic acid (1) would decrease the preclinical in vivo clearance, prevent formation of metabolite 2, and ultimately translate into improved human pharmacokinetic properties and lowering of the therapeutic dose, backup efforts guided by structure-based design were undertaken. These efforts were focused on the metabolism-directed optimization process and culminated in the discovery of 5-cyclopropyl-2-(4-fluorophenyl)-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)(methylsulfonyl)methyl)-N-methylbenzofuran-3-carboxamide (49, GSK8175), which is a clinical candidate.3 © XXXX American Chemical Society
One of the major challenges in discovery of drug candidates is the optimization of the lead compound for efficacy and druglike properties. Undoubtedly, the difficulty of any such project is to find compounds with multiple attributes, in this case, absence of benzylic metabolism while maintaining a useful antiviral profile, especially against the key clinically relevant mutant strains, which is a distinct feature of this particular problem. Optimization is more readily achieved by development of convergent synthetic routes in combination with structure- and property-based lead optimization. We have focused more on some notable structure-based medicinal chemistry design themes and metabolism-directed drug design, diversity-oriented modification, multiparameter optimization, and X-ray crystallography, and the inspirations these can bring to medicinal chemists.
2. STRUCTURE-BASED AND METABOLISM-DIRECTED DRUG DESIGN Structure-based drug design can potentially accelerate the development of new therapeutically useful compounds. The boronic acid moiety has been demonstrated to be a critical pharmacophore in potent inhibitors of the NS5B polymerase and is the structural basis for further optimization. Another highlight of this work is that the metabolism profile of GSK5852 was carefully characterized before advancing to structural optimization; it greatly increased the likelihood of finding a successful metabolically stable drug candidate. Received: March 10, 2019
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DOI: 10.1021/acs.jmedchem.9b00415 J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
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Figure 1. Graphical representation of the metabolism-directed optimization process, which culminated in the discovery of 49 as a clinical candidate. Metabolites 2 and 3 were identified in clinical plasma samples from human volunteers dosed with GSK5852 (1). The X-ray crystal structure of a benzoxaborole analogue (49) shows three ordered water molecules and key interactions to NS5B GT 1a 316Y protein (PDB code 6MVO). This structure has not yet been released.
al.,3 X-ray structures of a number of NS5B-ligand complexes were systematically examined and suggested that the boronic acid contributes to the binding with NS5B by forming the boronate complex and establishing multiple hydrogen bonds but no covalent interaction with the protein.
3. MAXIMIZING EXPANSION OF CHEMICAL SPACE BY DIVERSITY-ORIENTED STRUCTURAL MODIFICATIONS Exploration of structure−activity and structure−property relationships is a central task in lead optimization because if a molecule is not sufficiently effective, it will not become a drug candidate, irrespective of its other properties. Molecular diversity within chemical libraries certainly increases the probability that useful leads will be identified. In the paper by Chong et al.,3 three main goals were defined and over 600 analogues were prepared to expand the chemical diversity. Development of convergent synthetic routes that allowed efficient preparation of analogues during lead optimization has proved to be of significant value for exploitation of chemical space and compound prioritization.
6. CONCLUSION Optimization of failed clinical candidate drugs has emerged as an alternative approach to traditional drug discovery and development.4,5 The study published by GSK scientists is an excellent example of lead discovery that balances antiviral potency and metabolic stability with a number of medicinal chemistry strategies, which ultimately yielded an optimized, new clinical candidate.
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4. MULTIPARAMETER OPTIMIZATION Drug discovery is a multiparameter optimization process for efficacy and drug-like properties, and multiple properties must be balanced to reach the stage at which an active molecule can be considered for in vivo studies. Consequently, in this multiparameter optimization program to remove liabilities associated with 1, four criteria for newly designed compounds were proposed and prioritization of compounds was carefully considered. For example, the heteroaryl analogues 31 and 33 demonstrated low micromolar inhibition against CYP2C9, raising a potential barrier to their development. The boronic acid analogue 47 revealed a low micromolar activity against CYP2C9, while the benzoxaborole 49 clearly posed less risk of directly inhibiting the major CYPs, including CYP1A2 and CYP2D6. A low clearance in line with the heteroaryl series was observed in rat for 47 and 49, but 49 had slightly higher oral bioavailability than its boronic acid counterpart 47. Multiparameter optimization is still challenging in drug discovery and is mainly driven by experience, chemical knowledge, and intuition, not only because of synthetic considerations but also because of our limited ability to predict how compounds will interact with complex biological systems.
*P.Z.: e-mail,
[email protected]; phone, 086-53188382005. *X.L.: e-mail,
[email protected]; phone, 086-53188380270. ORCID
Peng Zhan: 0000-0002-9675-6026 Dongwei Kang: 0000-0001-9232-953X Author Contributions
All authors contributed to writing the manuscript. All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Natural Science Foundation of China (NSFC Grant 81573347), Young Scholars Program of Shandong University (YSPSDU Grant 2016WLJH32), Key Project of NSFC for International Cooperation (Grant 81420108027), and the Key Research and Development Project of Shandong Province (Grant 2017CXGC1401).
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5. UNIQUE BINDING MODES REVEALED BY X-RAY CRYSTALLOGRAPHY X-ray crystallography provided considerable assistance in validating the binding hypotheses. In the paper by Chong et
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DOI: 10.1021/acs.jmedchem.9b00415 J. Med. Chem. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.jmedchem.9b00415 J. Med. Chem. XXXX, XXX, XXX−XXX
