Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase

Tarver, James E.; Pabba, Praveen K.; Barbosa, Joseph; Han, Qiang; Gardyan, Michael; Brommage, Robert; Thompson, Andrea Y.; Schmidt, James M.; Wilson, Alan G. E.; He, Wei; Lombardo, Victoria K.; Carson, Kenneth G.

doi:10.1016/j.bmcl.2016.02.021

Cited by 38 publications

(74 citation statements)

References 12 publications

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“…hours. The plasma parameters from these mouse PK experiments (Cmax and AUC) are consistent with published preclinical PK data [5].…”

Section: Improved Synthesis Ofsupporting

confidence: 87%

“…LP-922056 (1) is an orally active inhibitor of Notum recently reported by Lexicon Pharmaceuticals [5,6].…”

Section: Lp-922056 (1)mentioning

confidence: 99%

“…Our first complete synthesis of 1 is presented in Scheme 1 (see Supporting Information for experimental procedures and characterisation data (File 1)). This 8-step sequence starts with 4-chlorothieno[3,2-4 d]pyrimidine (3), which is readily available from commercial suppliers, and generally follows published procedures [5,6] but with key modifications to increase yields/selectivities and significantly improve ease of purification of key intermediates. Our modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki-Miyaura cross-coupling reaction with MIDA-boronate 11 (5 → 6); and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one 12 Electrophilic bromination at C7 with N-bromosuccinamide gave 5 as the major regioisomer reproducibly on 100 mmol scale in modest yield (41-48 %).…”

Section: Improved Synthesis Ofmentioning

confidence: 99%

“…Pharmacokinetic (PK) data for 1 was generated in vivo in mouse to evaluate brain penetration (Table 1; Figure 1) (see Supporting Information Tables S1-S3 (File 1)). The route of administration and dose were selected to most closely match relevant published mouse disease model studies [5,7]. Following single oral dose (p.o.)…”

Section: Improved Synthesis Ofmentioning

confidence: 99%

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An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

Willis¹,

Bayle²,

Papageorgiou³

et al. 2019

Preprint

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Background: The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by mediating the depalmitoleoylation of Wnt proteins. LP-922056 (1) is an orally active inhibitor of Notum. We are investigating the role of Notum in modulating Wnt signalling in the central nervous system and wished to establish if 1 would serve as a peripherally restricted control. An accessible and improved synthetic route would allow 1 to become more readily available as a chemical tool to explore the fundamental biology of Notum and build target validation to underpin new drug discovery programs. Results: An improved, scalable synthesis of 1 is reported. Key modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki–Miyaura cross-coupling reaction with MIDA-boronate 11 (5 → 6); and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one (12) (6 → 7) as a mild selective electrophilic chlorination agent. This 7-step route has been reliably performed on large scale to produce multigram quantities of 1 in good efficiency and high purity. Pharmacokinetic studies in mouse showed CNS penetration of 1 is very low with brain:plasma concentration ratio of just 0.01. A small library of amides 17 were prepared from acid 1 to explore if 1 could be modified to deliver a CNS penetrant tool by capping off the acid as an amide. Although significant Notum inhibition activity could be achieved, none of these amides demonstrated the required combination of metabolic stability along with cell permeability without evidence of P-gp mediated efflux. Conclusion: Mouse pharmacokinetic studies demonstrate that 1 is unsuitable for use in models of disease where brain penetration is an essential requirement of the compound but would be an ideal peripherally restricted control. These data will contribute to the understanding of drug levels of 1 to overlay with appropriate in vivo efficacy endpoints, i.e. the PK-PD relationship. The identification of a suitable analogue of 1 (or 17) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models.

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“…hours. The plasma parameters from these mouse PK experiments (Cmax and AUC) are consistent with published preclinical PK data [5].…”

Section: Improved Synthesis Ofsupporting

confidence: 87%

“…LP-922056 (1) is an orally active inhibitor of Notum recently reported by Lexicon Pharmaceuticals [5,6].…”

Section: Lp-922056 (1)mentioning

confidence: 99%

Section: Improved Synthesis Ofmentioning

confidence: 99%

Section: Improved Synthesis Ofmentioning

confidence: 99%

See 2 more Smart Citations

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

Willis¹,

Bayle²,

Papageorgiou³

et al. 2019

Preprint

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“…Activity‐based small molecule screens for Notum inhibitors have been performed . We recently reported the development of 2‐phenoxyacetamides as Notum inhibitors .…”

Section: Introductionmentioning

confidence: 99%

Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum

Zhao

Ren

Hillier

et al. 2020

Journal of Pineal Research

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The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β‐catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N‐[2‐(5‐fluoro‐1H‐indol‐3‐yl)ethyl]acetamide that is structurally similar to melatonin came to our attention. We then soaked melatonin and its precursor N‐acetylserotonin into Notum crystals and obtained high‐resolution structures (≤1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid, and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µmol/L), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which upregulation of Wnt signalling may be beneficial.

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Recent Developments in Understanding the Role of Wnt Signaling in Skeletal Development and Disease

Zhong

Ethen

Williams

2018

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Stimulation of cortical bone formation with thienopyrimidine based inhibitors of Notum Pectinacetylesterase

Cited by 38 publications

References 12 publications

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

Structural characterization of melatonin as an inhibitor of the Wnt deacylase Notum

Recent Developments in Understanding the Role of Wnt Signaling in Skeletal Development and Disease

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