Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2<i>R</i>)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

Tucci, Fábio C.; Hu, Tao; Mesleh, Michael F.; Bokser, Allan; Allsopp, Eric; Gross, Timothy D.; Zhu, Yunfei; Struthers, R. Scott; Ling, Nicholas; Chen, Chen

doi:10.1002/chir.20198

Cited by 18 publications

(10 citation statements)

References 19 publications

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“…If the barrier to atropisomerization of a compound is low (class 2, Figure ), then one should consider developing the drug as a consistent and reproducible interconverting mixture . This is the case for Sch 40120 ( 11 ) (Scheme ), which is an inhibitor of 5-lipoxygenase.…”

Section: Atropisomeric Drugs: Medicinal Chemistry and Manufacturing P...mentioning

confidence: 99%

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Assessing Atropisomer Axial Chirality in Drug Discovery and Development

et al. 2011

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An underlying goal of drug discovery is to develop safe and stable substances that specifically target essential elements that cause disease. Molecular chirality adds an additional level of specificity and complexity in achieving this objective, as mirror image molecules are distinct substances and must be treated as such. Classical chiral-center enantiomers ( Figure 1A) have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics, and toxicity. 1 The cases of thalidomide 2 and perhexiline, 3 whose enantiomers differ dramatically with respect to toxicity and metabolic properties, emphasize the importance of addressing stereochemistry in drug development.In this Perspective, we address the pharmaceutical implications of a largely overlooked alternative source of drug chirality, atropisomerism, 4 which has the distinct feature of creating molecular chirality as a result of hindered rotation about a bond axis ( Figure 1B). Figure 1C shows space-filling models where it is evident that rotation about the vertical axis is hindered because of steric clashes between the bulky R1 and R2 groups with R3 and R4.Unlike compounds with classical chiral centers, which are often stable and which racemize via a bond breaking and making process, atropisomers racemize via an intramolecular dynamic process that only involves bond rotation. As bond rotation is time-dependent, racemization half-lives for atropisomers can vary dramatically between minutes to years, depending on the degree of steric hindrance, electronic influences, temperature, solvent, etc. Because of this time-dependent feature, drug discovery campaigns can become more complex, or may even be abandoned, when atropisomeric properties are observed. Atropisomerism frequently results as researchers strive to design more compact and conformationally constrained inhibitors. Even for courageous design and synthetic campaigns that attempt to develop atropisomeric compounds, important differences in properties have been reported for enantiomeric pairs, such as in vitro inhibition, crystallization, in vivo racemization rates, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. There are also examples of compounds that were unknowingly developed as a racemic mixture of atropisomers and required chiral detection experiments to finally reveal their existence. Overall, many view atropisomer chirality as a lurking menace with the potential to increase the cost of pharmaceutical research and development and to derail drug Figure 1. (A) Mirror-image enantiomers S and R arise from a classical chiral center (atom). (B) Other enantiomers S a and R a can arise from hindered rotation that creates a chiral axis. (C) Atropisomeric enantiomers S a and R a are shown as space-filling models. Reproduced with permission from ChemMedChem (LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O. Revealing atropisomer axial chirality in drug discovery. 2011, 6, 505À513,

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Section: Atropisomeric Drugs: Medicinal Chemistry and Manufacturing P...mentioning

confidence: 99%

“…A further example of this strategy is provided in Scheme , where removal of the methyl from the central ring resulted in changing from a class 2 compound to class 1 compound . These uracil compounds are potent antagonists of the human gonadotropin-releasing hormone receptor.…”

Section: Atropisomeric Drugs: Medicinal Chemistry and Manufacturing P...mentioning

confidence: 99%

Assessing Atropisomer Axial Chirality in Drug Discovery and Development

et al. 2011

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“…Further experiments using NMR and HPLC demonstrated that the interconversion between the two rotamers (aR-and aS-13) is fast, with a half-life estimated to be about 46 min at 37 °C in aqueous solution. 56 The X-ray crystal structure of 13 shows that the 2-fluoro-3-methoxyphenyl ring is nearly orthogonal to the uracil ring in the solid state (Figure 6), supporting the low-energy conformation and slow rotation of the biaryl bond. 55 An attempt to replace the 2-fluoro-3-methoxyphenyl group with various heteroaromatic groups to eliminate atropisomers while retaining potency resulted in some interesting compounds (Figure 7).…”

Section: Sar and Pharmacophore Of Uracil And Related Compoundsmentioning

confidence: 80%

“…In comparison, the des-fluoro analogue 14 ( K i = 2.3 nM) exhibits a single set of resonances under similar conditions. Further experiments using NMR and HPLC demonstrated that the interconversion between the two rotamers (a R - and a S - 13) is fast, with a half-life estimated to be about 46 min at 37 °C in aqueous solution . The X-ray crystal structure of 13 shows that the 2-fluoro-3-methoxyphenyl ring is nearly orthogonal to the uracil ring in the solid state (Figure ), supporting the low-energy conformation and slow rotation of the biaryl bond …”

Section: Sar and Pharmacophore Of Uracil And Related Compoundsmentioning

confidence: 86%

Non-Peptide Gonadotropin-Releasing Hormone Receptor Antagonists

et al. 2008

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“…However, no further publication regarding this class of derivatives has been reported since. Secondly, the methyl group at 6-position was removed [ 48 ]. A table of potent uracil derivatives without 6-methyl group were then prepared (compounds 19 – 21 ).…”

Section: Small Molecule Gnrh Receptor Antagonistmentioning

confidence: 99%

Recent Development of Non-Peptide GnRH Antagonists

et al. 2017

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The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market. The inherited issues associate with peptide agonists and antagonists have however, led to significant interest in developing orally active, small molecule, non-peptide antagonists. In this review, we will summarize all developed small molecule GnRH antagonists along with the most recent clinical data and therapeutic applications.

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Atropisomeric property of 1‐(2,6‐difluorobenzyl)‐3‐[(2R)‐amino‐2‐phenethyl]‐5‐(2‐fluoro‐3‐methoxyphenyl)‐6‐methyluracil

Cited by 18 publications

References 19 publications

Assessing Atropisomer Axial Chirality in Drug Discovery and Development

Assessing Atropisomer Axial Chirality in Drug Discovery and Development

Non-Peptide Gonadotropin-Releasing Hormone Receptor Antagonists

Recent Development of Non-Peptide GnRH Antagonists

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