Dihedral Angle in Medicinal Chemistry(Issue 5)
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By Jin Li
Dihedral angle-based drug design has been a commonly used approach for improving both the activity or selectivity of molecules and the conformation or orientation of molecules. For instance, small-molecule crystal data from the Cambridge Structural Database (CSD) revealed a dependence of the dihedral angle between the C=O and the phenyl ring on the size and polarity of R1 substituents (Figure 1). [1]
In the course of discovering a novel class of EZH2 inhibitors, there were two critical hypotheses: 1) the carbonyl oxygen makes an important hydrogen bond with the backbone NH of Tyr111 that is located approximately 50o above or below the plane of the phenyl ring; 2) the linker orients the dimethyl pyridone and phenyl rings into an optimal binding geometry. [1,2] With this in mind, a dihedral angle-based drug design strategy was used by introducing a Me or a Cl at the ortho position of benzamide in compounds 49 and 50 with activity increased by > 20-fold compared to compound 48. In conformation-restricted six-membered lactam compounds 51, 52 and 53, the same trend was observed. An X-ray crystal structure of compound 54 bound to EZH2 revealed that carbonyl oxygen forms a hydrogen bond with the backbone NH of Tyr111 as expected (Figure 2).
Docking compound 55 into AKT protein revealed that a critical hydrogen bond interaction between Glu278 and the nitrogen on the piperidine ring was missing. It was assumed that hydrogen bond interaction might be formed through deflecting the piperidine by a certain angle. A fluorine atom was incorporated at the ortho-position of amide in compound 56, and docking revealed that a 43.2o dihedral angle was observed between the phenyl flat and amide flat, leading to the nitrogen on piperidine ring close to Glu278 and forming a stable hydrogen bond (Figure 3). [3] Consistent with docking results, compound 56 had 5-fold more potent AKT1 activity than compound 55. It was also interesting that compound 56 had 16-fold less potent AKT2 activity than compound 55, the inhibition of which contributes to cutaneous toxicity.
Besides the impact on activity or selectivity, the dihedral angle can also influence the physicochemical properties of molecules significantly. [4] Molecular planarity and symmetry are known to influence crystal packing, and disruption of molecular planarity would be expected to decrease the efficiency of crystal packing, consequently changing physicochemical properties such as solubility, etc.
It was noteworthy that the disruption of molecular planarity of compound 57 by incorporating two steric methyl groups in compound 58 had greatly improved solubility by 350-fold (Figure 4). [5] A similar strategy has been widely used to disrupt the dihedral angle between two aromatic rings.
Besides biaryl structures as demonstrated in Figure 4, the increase of dihedral angle by steric hindrance was also useful for benzamide, anilide and phenylurea structures.
The transformation from compound 59 to compound 60 by adding chlorine caused an increase in solubility by at least 10-fold. The calculated LogP values of these two compounds are comparable which can’t explain the solubility difference. This can be understood in terms of a conformational effect constraining the urea group to be orthogonal to the aromatic ring in compound 60. In contrast, more planar conformations that may stack better in the solid state are permitted in the case of compound 59 (Figure 5). [6]
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In the course of discovering CDK inhibitors, it was found that the introduction of a methyl group in compound 62 at the ortho-position of dimethyl benzamide compound 61 led to a 230-fold increase in aqueous solubility (Figure 6). [7]
References
[1] Pei-pei Kung; et al. Design and synthesis of pyridine-containing 3,4-dihydroisoquinoline-1(2H)-ones as a novel class of enhancer of zeste homolog 2 (EZH2) inhibitors. J. Med. Chem. 2016, 59, 8306-8325.
[2] Pei-pei Kung; et al. Optimization of orally bioavailable enhancer of zeste homolog 2 (EZH2) inhibitors using ligand and property-based design strategies: identification of development candidate (R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497). J. Med. Chem. 2018, 61, 650-665.
[3] Jinxin Che; et al. Discovery of N-((3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a potent and selective Akt inhibitor that enables decrease of cutaneous toxicity. J. Med. Chem. 2021, 64, 12163-12180.
[4] Minoru Ishikawa; et al. Improvement in aqueous solubility in small molecule drug discovery programs by disruption of molecular planarity and symmetry. J. Med. Chem. 2011, 54, 1539-1554.
[5] Sauerberg P.; et al. Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo. J. Med. Chem. 2007, 50, 1495-1503.
[6] Leach A. G.; et al. Matched molecular pairs as a guide in the optimization of pharmaceutical properties: a study of aqueous solubility, plasma protein binding and oral exposure. J. Med. Chem. 2006, 49, 6672-6682.
[7] Jones C. D.; et al. Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 6486-6489.
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By Jin Li
Senior Director of PharmaBlock
Find out more at www.pharmablock.com