1365060-22-5

Basic information

• Product Name: LX-5061
• Synonyms: LX-5061;2-((6-chloro-7-cyclopropylthieno[3,2-d]pyriMidin-4-yl)thio)acetic acid
• CAS NO: 1365060-22-5
• Molecular Formula: C11H9ClN2O2S2
• Molecular Weight: 300.78
• Mol File: 1365060-22-5.mol

Chemical Properties

• Appearance: /
• CAS DataBase Reference: LX-5061(CAS DataBase Reference)
• NIST Chemistry Reference: LX-5061(1365060-22-5)
• EPA Substance Registry System: LX-5061(1365060-22-5)

Safety Data

• Hazardous Substances Data: 1365060-22-5(Hazardous Substances Data)

Upstream product

• 872190-91-5 7-bromo-4-methoxythieno[3,2-d]pyrimidine 
• 16228-99-2 4-methoxythieno[3,2-d]pyrimidine 
• 16269-66-2 4-chlorothieno[3,2-d]pyrimidine 
• 16234-10-9 3H-thieno[3,2-d]pyrimidin-4-one 
• 1384851-84-6 6-chloro-7-cyclopropyl-4-methoxythieno[3,2-d]pyrimidine 
• 1365062-51-6 7-cyclopropyl-4-methoxythieno[3,2-d]pyrimidine 
• 31169-27-4 7-bromo-4-chlorothieno[3,2-d]pyrimidine 
• 1365062-04-9 methyl 2-((6-chloro-7-cyclopropylthieno[3,2-d]pyrimidin-4-yl)thio)acetate 
• 1365062-53-8 C₉H₇ClN₂OS 

Relevant articles and documents

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

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 and selective electrophilic chlorination agent. This 7-step route from 16 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 a 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.

Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors

The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20–24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.

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

A group of small molecule thienopyrimidine inhibitors of Notum Pectinacetylesterase are described. We explored both 2-((5,6-thieno[2,3-d]pyrimidin-4-yl)thio)acetic acids and 2-((6,7-thieno[3,2-d]pyrimidin-4-yl)thio)acetic acids. In both series, highly potent, orally active Notum Pectinacetylesterase inhibitors were identified.

INHIBITORS OF NOTUM PECTINACETYLESTERASE AND METHODS OF THEIR USE

Compounds are disclosed for the treatment, management and prevention of diseases and disorders affecting the bone. Particular compounds are potent inhibitors of Notum Pectinacetylesterase, and are of the formula: wherein E, G, Y, Z, R1, R2, and R3 are defined herein.