Viewpoint Cite This: J. Med. Chem. XXXX, XXX, XXX−XXX
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The Chimera That Curbs Appetite Leonard G. Luyt*,†,‡ †
Departments of Chemistry, Oncology, and Medical Imaging, University of Western Ontario, London, ON N6A 4L6, Canada London Regional Cancer Program, Lawson Health Research Institute, London, ON N6A 5W9, Canada
‡
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ABSTRACT: A chimeric drug design approach, merging the structure of an antagonist and an inverse agonist, results in a new molecular scaffold for targeting the ghrelin receptor (GHSR).
Chimeric drug design is an approach used for the rational design of compounds that bring together two or more desirable pharmacological traits.5,6 While small molecule chimeric drugs at times hold together two pharmacophore units by using a central and nonfunctional scaffold, in this case the authors overlapped the two structures through a common amino group, which is critical for receptor interaction through a salt bridge to Glu124 of GHSR. There are certainly implications for using this approach for other chimeric designs for GHSR and likely for other GPCR targets in order to control signaling bias. In the work on GHSR inverse agonists presented in this issue, the hybridization of an antagonist pharmacophore with an established inverse agonist pharmacophore, predicted to bind deeper in the receptor binding site, resulted in the discovery of a unique chemotype and is predicted to provide favorable pharmacokinetic and ADME properties. For those developing new GHSR ligands, an important objective is to discover molecules with improved brain access in order to provide higher CNS exposure. This has proven difficult, as demonstrated by two studies investigating radiolabeled GHSR small molecules and evaluating brain uptake and receptor binding by means of PET (positron emission tomography) imaging. Potter et al. reported a carbon-11 radiolabeled antagonist that binds GHSR (Ki = 22 nM) and was found to have specific accumulation in the hypothalamus, although the relatively high nonspecific binding within the brain suggests that an improved ligand is required.7 More recently, Kawamura et al. described a carbon-11 labeled GHSR partial agonist based upon a piperazine scaffold, with improved receptor affinity (Ki = 7.0 nM); however, the high cLogD of >5 prevented this compound from having significant brain uptake.8,9 The results reported by Daina et al.10 indicates significant brain exposure for their chimeric inverse agonist in rats, with a brain/plasma (B/P) ratio of 1.86 at 2 h. Although this compound has only moderate oral bioavailability (F = 27%), pharmacological evaluation demonstrated that this inverse agonist counteracted the expected increase in food intake in mice when dosed with a GHSR agonist (anamorelin), with either intraperitoneal (ip) or oral (po) administration. This provides additional support for the hypothesis that this inverse
Drug development activity has continued to escalate in intensity for targeting the growth hormone secretagogue receptor (GHSR), also referred to as the ghrelin receptor. This G-protein-coupled receptor (GPCR) is attracting attention due to its therapeutic potential for treating many metabolism-related diseases, including obesity, type 2 diabetes, cachexia, anorexia, and others. The increasing complexity in the understanding of drug interactions with GPCRs has provided the medicinal chemist with many alternative approaches to designing a chemical entity for binding to the receptor. While orthosteric ligands remain at the forefront, binding to allosteric sites of the receptor or engaging with receptor homo- and heterodimers can provide selectivity in modulating responses and downstream signaling. Even within the orthosteric binding site there is an ability to fine-tune interactions, with molecular modifications moving a ligand from being an agonist to antagonist to inverse agonist. This is of particular relevance to the GHSR, since this receptor has an unusually high constitutive activity,1 suggesting that an inverse agonist may provide additional in vivo efficacy as compared to that provided by an antagonist. The development of inverse agonists is especially valuable in such a setting, where control over signaling bias can result in selective ligands with improved functional outcome without undesirable effects.2,3 Antagonists and inverse agonists for the GHSR hold promise as a therapeutic approach for appetite reduction and weight loss.4 While a number of promising inverse agonist drug candidates for the GHSR have been reported, they have a limited ability to cross the blood−brain barrier (BBB). A new molecular scaffold for targeting the GHSR has now been reported by Daina et.al.10 in this issue of the Journal of Medicinal Chemistry. The unique design process for discovering this inverse agonist makes the scientific story distinctive. Two molecular templates were used, one consisting of the inverse agonist from Pfizer (PF-05190457, Figure 1) and the other an antagonist from Helsinn (H0700, Figure 1). A structure-based hypothesis was developed, with both ligands binding to the same acidic residue (Glu124) in the receptor as an anchor point. The inverse agonist extends deeper into the orthosteric binding site, which is believed to result in strong π-stacking interactions, thereby preventing receptor activation due to changes in extracellular receptor motion. By combination of this deeper binding portion of the inverse agonist with the strong affinity of the antagonist, a chimeric scaffold was created. © XXXX American Chemical Society
Received: November 19, 2018
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DOI: 10.1021/acs.jmedchem.8b01809 J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
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Figure 1. Chimeric design. Merging of inverse agonist PF-5190457 with antagonist H0700 results in a central acting inverse agonist for the GHSR. Novel Ghrelin Receptor Inverse Agonists as Potential Treatment against Obesity-Related Metabolic Diseases. J. Med. Chem. 2018, DOI: 10.1021/acs.jmedchem.8b00794
agonist can act on the CNS as a therapeutic for obesity-related metabolic disease.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Twitter: @LuytGroup. Web site: www. LuytGroup.com. ORCID
Leonard G. Luyt: 0000-0002-0941-4731
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REFERENCES
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DOI: 10.1021/acs.jmedchem.8b01809 J. Med. Chem. XXXX, XXX, XXX−XXX
