Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitor with predicted blood–brain barrier permeability

Borsari, Chiara; Keles, Erhan; Treyer, Andrea; Pascale, Martina De; Hebeisen, Paul; Hamburger, Matthias; Wymann, Matthias P.

doi:10.1039/d0md00408a

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…This study will elucidate if pharmacological mTOR inhibition during critical neurodevelopmental time windows alleviates cognitive impairments in mTORopathies. Thereof, there is ongoing effort to develop more stable rapalogs with better brain permeability and less systemic toxicity [174][175][176].…”

Section: Mtoropathiesmentioning

confidence: 99%

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Vasić

Jones

Haslinger

et al. 2021

Genes

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Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.

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Section: Mtoropathiesmentioning

confidence: 99%

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Vasić

Jones

Haslinger

et al. 2021

Genes

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“…25 classified as the first pyrimido‐pyrrolo‐oxazine with potential application in the treatment of CNS disorders. [28b] The purine compound 20 and thiazolo[5,4‐ d ]pyrimidine derivative 21 showed good permeability with no P‐gp mediated efflux assessed using a MDCK‐MDR1 assay. 21 presented desirable brain permeability in PK studies and efficacy in a mouse model of Tuberous Sclerosis Complex (TSC).…”

Section: Effect Of Physicochemical Descriptors On Brain Permeabilitymentioning

confidence: 99%

“…Extensive SAR studies allowed to pinpoint compounds 22 – 25 as highly selective mTOR inhibitors with a variety of profiles regarding brain penetration and physicochemical properties. [28] Among them, 25 [28b] displayed the highest selectivity [ K i (PI3Kα)/ K i (mTOR) >600; Figure 4 e and 4 f]. For the compounds’ classes described in this sub‐chapter, substituted and sterically hindered morpholines are pivotal to direct mTOR selectivity, but alone they are not able to yield highly selective inhibitors.…”

Section: Structural Analysis Of Torkimentioning

confidence: 99%

“…While the tricyclic compounds 22 and 24 did not cross the BBB, [28a] the conformationally restricted derivative 25 showed predicted BBB permeability in a MDCK‐MDR1 permeability in vitro assay. 25 classified as the first pyrimido‐pyrrolo‐oxazine with potential application in the treatment of CNS disorders [28b] . The purine compound 20 and thiazolo[5,4‐ d ]pyrimidine derivative 21 showed good permeability with no P‐gp mediated efflux assessed using a MDCK‐MDR1 assay.…”

Section: Effect Of Physicochemical Descriptors On Brain Permeabilitymentioning

confidence: 99%

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Chemical and Structural Strategies to Selectively Target mTOR Kinase

2021

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Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First-generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP-competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP-competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3-kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds' ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders.

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“…While 3-hydroxymethylmorpholines comprise two nucleophilic groups, sulfamidates can serve as retrosynthetic equivalents of synthon I (Figure 2b). Such sulfamidates are synthetic analogs of aziridines 31 and useful building blocks for the introduction of morpholines in a stereospecific [32][33][34] and even annulating 17,24 fashion.…”

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confidence: 99%

Stereospecific Synthesis of Substituted Sulfamidates as Privileged Morpholine Building Blocks

et al. 2022

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Morpholine is a heterocyclic moiety widely used in medicinal chemistry as a building block. It has unique physicochemical properties, as it can improve both pharmacokinetic and pharmacodynamic properties of active pharmaceutical ingredients. However, the efficient synthesis of enantiomerically pure morpholine building blocks remains challenging. Herein, we report a synthesis of optically pure 3-hydroxymethylmorpholine building blocks, as well as their sulfamidates, exploiting a stereospecific strategy from chiral pool material.

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Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitor with predicted blood–brain barrier permeability

Abstract: Here we present the first pyrimido-pyrrolo-oxazine-based mTOR kinase inhibitor (11) predicted to penetrate the blood brain barrier (BBB). Thus, 11 has a potential in treatments of neurological disorders.

Cited by 7 publications

References 23 publications

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Chemical and Structural Strategies to Selectively Target mTOR Kinase

Stereospecific Synthesis of Substituted Sulfamidates as Privileged Morpholine Building Blocks

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