Investigation of the Mechanism of Racemization of Litronesib in Aqueous Solution: Unexpected Base‐Catalyzed Inversion of a Fully Substituted Carbon Chiral Center

Baertschi, Steven W.; Jansen, Patrick J.; Montgomery, Robert M.; Smith, William K.; Draper, Jerry R.; Myers, David P.; Houghton, Peter G.; Sharp, V. Scott; Guisbert, Andrea L.; Zhuang, Hong; Watkins, Michael A.; Stephenson, Gregory A.; Harris, Thomas M.

doi:10.1002/jps.23918

Cited by 5 publications

(4 citation statements)

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“…Litronesib, 14a, is an investigational compound that inhibits Eg5 and has been investigated as a treatment for several types of malignancy. [31] An unexpected loss of chiral integrity was observed upon storage of this compound. The chiral centre in this case is fully substituted and so the racemization was surprising.…”

Section: <>mentioning

confidence: 96%

“…The compounds sold as single isomers but predicted to racemize are cycloserine (26), bentiromide (27), valacyclovir (28), ropivacaine (29), clopidogrel (2), brinzolamide (30), levobupivacaine (8), levocetirizine (9) and safinamide (31). Two of these nine compounds (27 and 8) are annotated as discontinued (as distinct from withdrawn).…”

Section: Compounds Predicted At Risk Of Racemization Distributed As Amentioning

confidence: 99%

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The problem of racemization in drug discovery and tools to predict it

Ballard

Narduolo

Ahmad

et al. 2019

Expert Opinion on Drug Discovery

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IntroductionRacemization has long been an ignored risk in drug development, probably because of a lack of convenient access to good tools for its detection and an absence of methods to predict racemization risk. As a result, the potential effects of racemization have been systematically underestimated. Areas coveredHerein, the potential effects of racemization are discussed through a review of drugs for which activity and side effects for both enantiomers are known. Subsequently, drugs known to racemize are discussed and we review methods to predict racemization risk.Application of a method quantitatively predicting racemization risk to databases of compounds from the medicinal chemistry literature shows that success in clinical trials is negatively correlated with racemization risk. Expert opinionIt is envisioned that a quantitative method of predicting racemization risk will remove a blind spot from the drug development pipeline. Removal of the blind spot will make drug development more efficient and result in less late-stage attrition of the drug pipeline. KeywordsRacemization; quantitative prediction; stability; enantiomers; risk; Adrenaline, 10, can be used to induce vasoconstriction at the site of injection of local anaesthetics and the L-form is 10 times more effective than the D-form.[18] Certain aromatase inhibitors, such as fadrozole, 11, have significantly different activities for each of the two enantiomers; S-fadrozole is most active for instance. [19] Other studies have investigated the pharmacokinetic properties of enantiomers.Ketoprofen, 12, is a non-steroidal anti-inflammatory and its delivery via a trans-dermal route has been considered.[20] When used orally, it is delivered as a racemate but stereoselective skin permeation might favour its use as a single enantiomer for this alternative delivery route. Studies showed the racemate to be higher melting than the individual enantiomers and x-ray diffraction patterns support the racemate having a different solid form than the individual enantiomers suggesting that the two enantiomers co-crystallize and are both present in the unit cell. When 0.05 M solutions of each of the enantiomers was applied to mouse skin, no difference in permeation was detected between enantiomers or racemate.Further studies supported no stereoselectivity for skin permeability for ketoprofen.Ketorolac, 13, was investigated in a pharmacokinetic study in healthy volunteers. [21] Following intravenous injection, the concentration of the two enantiomers was monitored separately. This showed that S-ketorolac is cleared more rapidly than the R enantiomer leading to higher exposure to R-ketorolac. Surveys* N ALK ALK * OH * H * NH 2 FDA statement on the development of new stereoisomeric drugs. * 12. Eriksson T, Bjorkman S, Roth B, Fyge A, Hoglund P. Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality 1995;7:44-52. This paper provides rare, and therefore very valuable, kinetic data for racemization in huma...

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Section: <>mentioning

confidence: 96%

Section: Compounds Predicted At Risk Of Racemization Distributed As Amentioning

confidence: 99%

The problem of racemization in drug discovery and tools to predict it

Ballard

Narduolo

Ahmad

et al. 2019

Expert Opinion on Drug Discovery

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“…Al oss of chiral purity wasobserved for the Eg5 inhibitor R-litronesib (8)d uring storagei naliquid formulation. [33] This racemisationi sb ase-catalysed, despite the stereogenic centre being quaternary.S tudies revealed that the racemisation dependso np Hb ut does not depend on buffer identity,t hat is, specific-base catalysis. On the basis of this observation, a mechanism involving equilibrium deprotonation of the sulphonamide was proposed, which is followed by am ulti-step ylidmediated process featuring ar elayo fi onized groups (Scheme 9).…”

Section: Specific-base Catalysismentioning

confidence: 99%

“…[65] Liquid chromatographic techniques, such as chiral HPLC, are used widely for studying stereochemistry and racemisation. [33,38,50,88] Typical approaches involve either full separation of the enantiomerso rp eak shapea nalysisf or compounds racemising in the HPLCe luent. [10,89] Al iquid-chromatography methodh as been adapted to include an artificial membrane intendedt om imic cell membranes, an environment that many drugs partitioni nto.…”

Section: Experimental Techniques For Studying Racemisationmentioning

confidence: 99%

Racemisation in Chemistry and Biology

Ballard

Narduolo

Ahmed

et al. 2020

Chemistry A European J

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The two enantiomers of a compound often have profoundly different biological properties and thus their liability to racemisation in aqueous solutions is an important piece of information. The authors reviewed the available data concerning the process of racemisation in vivo, in the presence of biological molecules (e.g., racemase enzymes, serum albumin, cofactors and derivatives) and under purely chemical but aqueous conditions (acid, base and other aqueous systems). Mechanistic studies are described critically in light of reported kinetic data. The types of experimental measurement that can be used to effectively determine rate constants of racemisation in various conditions are discussed and the data they provide is summarised. The proposed origins of enzymatic racemisation are presented and suggest ways to promote the process that are different from processes taking place in bulk water. Experimental and computational studies that provide understanding and quantitative predictions of racemisation risk are also presented.

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Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors

Talapatra

Tham

Guglielmi

et al. 2018

European Journal of Medicinal Chemistry

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The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

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Investigation of the Mechanism of Racemization of Litronesib in Aqueous Solution: Unexpected Base‐Catalyzed Inversion of a Fully Substituted Carbon Chiral Center

Cited by 5 publications

References 23 publications

The problem of racemization in drug discovery and tools to predict it

The problem of racemization in drug discovery and tools to predict it

Racemisation in Chemistry and Biology

Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors

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