Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a motor neuron disease, typically resulting from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Nusinersen/SPINRAZA, a splice-switching oligonucleotide that modulates SMN2 (a paralog of SMN1) splicing and consequently increases SMN protein levels, has a therapeutic effect for SMA. Previously reported small-molecule SMN2 splicing modulators such as risdiplam/EVRYSDI and its analog SMN-C3 modulate not only the splicing of SMN2 but also that of secondary splice targets, including forkhead box protein M1 (FOXM1).

Incidental ethmoidal dural arteriovenous fistula coexisting with a pituitary adenoma exacerbating post-transsphenoidal epistaxis.

A 64 year-old man with pituitary adenoma developed massive epistaxis after an uneventful endoscopic transsphenoidal surgery. Angiography showed extravasation from the sphenopalatine artery, to which embolisation was performed. An incidentally coexisting ethmoidal dural arteriovenous fistula supplied by the ophthalmic artery aberrantly originated from the middle meningeal artery caused increased haemorrhage.

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level.

Rh(I)-catalyzed CO gas-free cyclohydrocarbonylation of alkynes with formaldehyde to alpha,beta-butenolides.

The rhodium(I)-catalyzed reaction of alkynes with formaldehyde proceeds via the double incorporation of a carbonyl moiety from formaldehyde, resulting in a CO gas-free cyclohydrocarbonylation leading to alpha,beta-butenolides.

Secondary benzylation using benzyl alcohols catalyzed by lanthanoid, scandium, and hafnium triflate.

The combination of a secondary benzyl alcohol and a metal triflate (e.g., La, Yb, Sc, and Hf triflate) in nitromethane was a highly effective secondary-benzylation system.

CO-transfer carbonylation reactions. A catalytic Pauson-Khand-type reaction of enynes with aldehydes as a source of carbon monoxide.

The reaction of enynes with aldehydes in the presence of a catalytic amount of [RhCl(cod)](2)/dppp results in the Pauson-Khand-type reaction without the use of gaseous carbon monoxide to give bicyclic cyclopentenones in high yields (14 examples). Aldehydes serve as a source of carbon monoxide, and their carbonyl moiety is transferred to enynes, resulting in the formation of the carbonylated products. This reaction represents the first example of a CO-transfer carbonylation.