1610772-26-3

Upstream product

• 5720-05-8 4-methylphenylboronic acid 
• 56844-12-3 6-bromo-4-chlorothieno[2,3-d]pyrimidine 
• 14080-50-3 thieno[2,3-d]pyrimidin-4(3H)one 
• 56844-40-7 6-bromothieno[2,3-d]pyrimidin-4(3H)-one 
• 1345882-89-4 ethyl 2-amino-5-(4-methylphenyl)-3-thiophenecarboxylate 

Downstream Products

• 1610771-89-5 (((6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)phosphonic acid 
• 1610772-21-8 (2-(6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)ethyl)phosphonic acid 
• 1615230-74-4 diethyl (((6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)amino)methyl)phosphonate 
• 1615230-71-1 (2-((6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)amino)ethyl)phosphonic acid 
• 1615230-72-2 2-((6-(p-tolyl)thieno[2,3-d]pyrimidin-4-yl)amino)acetic acid 

Relevant academic research and scientific papers

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors

The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.

Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase

The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacophore requirements for allosteric inhibition.

Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: Implications to drug discovery for neurodegenerative diseases

Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration.