Synthesis and Biological Evaluation of Novel 2,4-Diaminoquinazoline Derivatives as SMN2 Promoter Activators for the Potential Treatment of Spinal Muscular Atrophy was written by Thurmond, John;Butchbach, Matthew E. R.;Palomo, Marty;Pease, Brian;Rao, Munagala;Bedell, Louis;Keyvan, Monica;Pai, Grace;Mishra, Rama;Haraldsson, Magnus;Andresson, Thorkell;Bragason, Gisli;Thosteinsdottir, Margret;Bjornsson, Jon Mar;Coovert, Daniel D.;Burghes, Arthur H. M.;Gurney, Mark E.;Singh, Jasbir. And the article was included in Journal of Medicinal Chemistry in 2008.SDS of cas: 120121-01-9 This article mentions the following:
Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene (SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chem. effort was to identify small-mol. activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chem. effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazolines that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. A structure-guided approach was used to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound, the [(fluorobenzyl)piperidinylmethoxy]quinazolinediamine I, was identified as having high potency and 2.3-fold induction of the SMN2 promoter. I possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. I up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, I induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA. In the experiment, the researchers used many compounds, for example, (R)-1-(3-Chlorophenyl)ethanol (cas: 120121-01-9SDS of cas: 120121-01-9).
(R)-1-(3-Chlorophenyl)ethanol (cas: 120121-01-9) belongs to alcohols. Under appropriate conditions, inorganic acids also react with alcohols to form esters. To form these esters, a wide variety of specialized reagents and conditions can be used. Grignard and organolithium reagents are powerful tools for organic synthesis, and the most common products of their reactions are alcohols.SDS of cas: 120121-01-9
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