Matrix metalloproteinase-12 (MMP-12) selective inhibitors could play a role in the treatment of lung inflammatory and cardiovascular diseases. In the present study, the previously reported 4-methoxybiphenylsulfonyl hydroxamate and carboxylate based inhibitors (1b and 2b) were modified to enhance their selectivity for MMP-12. In the newly synthesized thioaryl derivatives, the nature of the zinc binding group (ZBG) and the sulfur oxidation state were changed. Biological assays carried out in vitro on human MMPs with the resulting compounds led to identification of a sulfide, 4a, bearing an N-1-hydroxypiperidine-2,6-dione (HPD) group as new ZBG. Compound 4a is a promising hit compound since it displayed a nanomolar affinity for MMP-12 with a marked selectivity over MMP-9, MMP-1, and MMP-14. Solution complexation studies with Zn were performed to characterize the chelating abilities of the new compounds and confirmed the bidentate binding mode of HPD derivatives. X-ray crystallography studies using MMP-12 and MMP-9 catalytic domains were carried out to rationalize the biological results.
Objective: To evaluate the long-term stability of intratympanic steroids and investigate the ‘real’ impact of sudden\ud
sensorineural hearing loss on patients.\ud
Method: A total of 14 patients treated with intratympanic steroids were evaluated by audiometric and vestibular\ud
examinations. The modified Glasgow Benefit Inventory was used to evaluate quality of life changes after\ud
intratympanic steroid treatment.\ud
Results: There was no significant difference between pure tone average post-intratympanic steroids and at follow\ud
up. The general Glasgow Benefit Inventory score was not significantly associated with the presence of tinnitus\ud
or dizziness, or with patient age. The change in pure tone average after intratympanic steroid treatment did not\ud
correlate with social or physical scores, but correlated strongly with the general Glasgow Benefit Inventory score\ud
( p = 0.0023). Intratympanic steroid administration led to a stable improvement in hearing. Quality of life\ud
assessment showed that patients can feel satisfaction regardless of the hearing outcome. Patients who regained a\ud
social hearing level expressed greater satisfaction than patients without serviceable hearing. Overall, quality of\ud
life improvement was not related to hearing improvement.\ud
Conclusion: Sudden sensorineural hearing loss is devastating. Considering the audiological effects alone ignores\ud
the ‘human’ perspective. Audiological success can correlate with poor quality of life outcome
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.