【MedChem Spark】Polarized C-H as Nonconventional Hydrogen Bond Donor(Issue 3)
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By Jin Li
Canonical hydrogen bond donors, N-H and O-H, play key roles in interactions between molecules and proteins and exist in substantial drug and clinical candidate molecules, especially in kinase inhibitors which have a N-H forming a hydrogen bond with hinge region. Issues associated with canonical hydrogen bond donors are their potentially negative influences on aqueous solubility, permeability, glucosidation metabolism, etc. In order to circumvent this, C-H in heteroaromatic rings containing nitrogen is often used as nonconventional hydrogen bond donors due to the increased acidity of the involved C-H hydrogen. For example, C-H in pyrazine was found to form nonconventional hydrogen bonds with protein backbone and –COOH residues (Figure 1). [1]
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In order to discover BBB-penetrant LRRK2 inhibitors, the replacement of indazole N1-H in compound 24 with imidazo[1,5-a]pyridine core C-H in compound 25 and “reverse indazole” C3-H in compound 26 was explored. [2] Despite the anticipated loss in potency, significantly reduced P-gp efflux was observed for compound 26, positively differentiating this core. Further optimization of compound 26 afforded highly potent, selective and BBB-penetrant LRRK2 inhibitors. A nonconventional hydrogen bond between C3-H in indazole with backbone C=O of LRRK2 Glu85 was demonstrated in an X-ray structure of one of LRRK2 inhibitors bound to LRRK2 (Figure 2).
Polarization of the aryl C-H to increase the hydrogen bonding potential was believed to be necessary to bring about sufficient TYK2 activity and two-point binding. With this strategy in mind, several [5,6]-fused heteroaromatic systems, including imidazopyridine scaffold in compound 27, [1,2,4] triazoles [1,5]pyridine scaffolds in compound 28, [1,2,4]triazole[4,3]pyridine scaffold in compound 29 and pyrazole[1,5]pyrazine scaffold in compound 30, were designed and evaluated (Figure 3). [3] Among the above scaffolds, the pyrazole[1,5]pyrazine scaffold was of particular interest due to the calculated increased polarization of the C-H for hydrogen bond donor properties. Consistent with the calculation result, pyrazole[1,5]pyrazine analog 30 was found to be a potent TYK2 enzyme inhibitor at 10 nM. An X-ray crystal structure of compound 30 bound to TYK2 confirmed the expected binding mode with polarized C7-H engaged in an interaction with the backbone C=O of TYK2 Val981. As proved by this case study, pyrazole[1,5]pyrazine scaffold could be potentially used as a kinase hinge binding motif for discovery of kinase inhibitors, especially for that requiring BBB-penetration.
To better understand the origin of the increased potency and subtype selectivity of CK1δ inhibitor 31, an X-ray structure of compound 31 bound to CK1δ was obtained. It was found that polarized C-H of lactam motif formed a nonconventional hydrogen bond with the backbone C=O of Leu85. Meanwhile, polarized C-H of pyridine formed an additional nonconventional hydrogen bond with the backbone C=O of Glu83 (Figure 4). [4] Scaffold 6,7-dihydropyrrolo[3,4-b]pyridine-5-one could be utilized in the discovery of inhibitors of more kinases since it potentially affords three hydrogen bonds with kinase hinge region.
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References
[1] Martin Juhas; et al. Molecular interactions of pyrazine-based compounds to proteins. J. Med. Chem. 2020, 63, 8901-8916.
[2] David A. Candito; et al. Discovery and optimization of potent, selective, and brain-penetrant 1-heteroaryl-1H-indazole LRRK2 kinase inhibitors for the treatment of Parkinson’s disease. J. Med. Chem. 2022, 65, 16801-16817.
[3] Brian S. Gerstenberger; et al. Discovery of tyrosine kinase 2 (TYK2) inhibitor (PF-06826647) for the treatment of autoimmune diseases. J. Med. Chem. 2020, 63, 13561-13577.
[4] Travis T. Wager; et al. Identification and profiling of a selective and brain penetrant radioligand for in vivo target occupancy measurement of Casein kinase (CK1) inhibitors. ACS Chem. Neurosci. 2017, 8, 1995-2004.
About Author
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By Jin Li
Senior Director of PharmaBlock
Find out more at www.pharmablock.com