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Lowering Lipophilicity by Adding Carbon: One Carbon Bridges of Morpholines and Piperazines Sebastien L. Degorce, Michael Bodnarchuk, Iain Cumming, and James S. Scott J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01148 • Publication Date (Web): 06 Sep 2018 Downloaded from http://pubs.acs.org on September 6, 2018
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Journal of Medicinal Chemistry
Lowering Lipophilicity by Adding Carbon: One Carbon Bridges of Morpholines and Piperazines Sébastien L. Degorce, * Michael S. Bodnarchuk, Iain A. Cumming and James S. Scott. Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, Unit 310 Darwin Building, Cambridge CB4 0WG, United Kingdom.
KEYWORDS: lipophilicity, permeability, morpholine, piperazine, conformation, matched molecular pair analysis.
ABSTRACT
In this article, we report our investigation of a phenomenon by which bridging morpholines across the ring with one carbon tethers leads to a counter-intuitive reduction in lipophilicity. This effect was also found to occur in piperazines and piperidines, and lowered the measured logD7.4 of the bridged molecules by as much as −0.8, relative to their unbridged counterparts. As lowering lipophilicity without introducing additional heteroatoms can be desirable, we believe this potentially provides a useful tactic to improve the drug-like properties of molecules containing morpholine, piperazine and piperidine-like motifs.
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INTRODUCTION Morpholines and their derivatives are a commonly encountered motif in drug discovery projects. They may be used as groups to enhance potency through molecular interactions with a target protein (e.g. the ether oxygen acts as a key binding motif in inhibitors of lipid kinases such as some PI3K isoforms, DNAPK, mTOR or ATR)1 or as groups to modulate physico-chemical properties as the weak basicity of morpholine (e.g. N-methyl morpholine, pKa = 7.4) is similar to the pH of blood and often brings enhancements in solubility without compromising permeability to the extent seen with stronger bases. As a result, medicinal chemists have frequently utilized morpholines as part of drug discovery programs and subsequently substituted them to further optimize molecular properties. During recent medicinal chemistry discovery projects, we observed that by bridging morpholines with a one carbon linker (effectively the net addition of a single carbon atom), lipophilicity (measured as the distribution coefficient between octanol and buffered water, logD7.4) was counter-intuitively lowered. A selected set of molecules related to a series of recently disclosed IRAK4 inhibitors2 is shown in Table 1 for illustrative purposes: the observed logD7.4 of the bridged analogues 1d and 1e was significantly lower (∆logD7.4 = −0.7) than that of the parent morpholine 1a. This was in contrast with the monomethyl analogues 1b and 1c which showed an increase in lipophilicity (∆logD7.4 = +0.4), and was not well predicted by partition coefficient predictors such as clogP (∆clogP = +0.3) or ACDlogP (∆ACDlogP = −0.1), although the latter predicted a slight decrease. As measured logD7.4 is a composite of logP and pKa (for monobases logD7.4=logP−log[1+10(pKa−7.4)]), we measured the pKa’s of 1a and 1e and found that bridged morpholine 1e was significantly more basic than 1a (∆pKa = +0.6), in line with ACD predictions (∆ACDpKa = +0.7). This suggested that at least some of the lipophilicity lowering
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Journal of Medicinal Chemistry
effect was attributable to an increase in basicity.
Predictive programs such as ACDlogD
considerably underestimated the lipophilicity for these molecules, although the magnitude of the change for addition of the methyl in 1b and 1c agreed well with experimental data (∆logD7.4 ~ ∆ACDlogD ~ +0.5) and the ACD program correctly predicted that the bridged molecules will be less lipophilic (∆ACDlogD = −1.0, ∆logD7.4 = −0.7), albeit to a greater extent than measured. This phenomenon caught our attention since ways to lower lipophilicity without resorting to the introduction of additional heteroatoms are useful so that other properties are not compromised. For example, lowering lipophilicity by introducing hydrogen bond donors or acceptors usually results in increased polar surface area and can adversely impact permeability (and thus absorption) beyond the amount expected based on the logD reduction alone.3 Lowering lipophilicity through increasing basicity or acidity may impact other parameters, such as permeability/absorption, and may also introduce undesired activity such as hERG inhibition in the case of strong bases, or high levels of plasma protein binding in the case of acids. In the morpholine examples presented in table 1 however, no adverse effect attributable to the increased basicity of bridged morpholines 1d-e was observed on properties like hERG, permeability or rat hepatocytes turnover (e.g. R,R enantiomer 1d was actually found to be more metabolically stable than morpholine 1a).
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Table 1. Examples of morpholine derivatives and selected lipophilicity-related properties.
Entry
R
ACDlogP a (∆ACDlogP)
ACDlogD7.4 a logD7.4 b ACD pKa a pKa c hERG Caco2 d e (∆ACDlogD) (∆logD7.4) (∆ACDpKa) (∆pKa) pIC50 A2B Papp
1a
2.4 (0.0)
0.9 (0.0)
2.6 (0.0)
7.5 (0.0)
1b
2.9 (+0.5)
1.4 (+0.5)
3.1 (+0.5)
1c
2.9 (+0.5)
1.4 (+0.5)
1d
2.3 (−0.1)
1e
2.3 (−0.1)
7.5 (0.0)
Rat CLint f
