Publication
Azetidine-2,4-diones (4-oxo-beta-lactams) as scaffolds for designing elastase inhibitors
| dc.contributor.author | Mulchande, Jalmira | |
| dc.contributor.author | Guedes, Rita C. | |
| dc.contributor.author | Tsang, Wing-Yin | |
| dc.contributor.author | Page, Michael I. | |
| dc.contributor.author | Moreira, Rui | |
| dc.contributor.author | Iley, Jim | |
| dc.date.accessioned | 2015-12-30T10:18:34Z | |
| dc.date.available | 2015-12-30T10:18:34Z | |
| dc.date.issued | 2008 | |
| dc.description.abstract | A new class of inhibitors 4-oxo-beta-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-beta-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl-N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett p-value of 0.65. Compared with a p-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of similar to 5 x 10(5) M-1 s(-1). | |
| dc.format | application/pdf | |
| dc.identifier.citation | JOURNAL OF MEDICINAL CHEMISTRY. - Vol. 51, n. 6 (2008), p. 1783-1790 | |
| dc.identifier.doi | http://dx.doi.org/10.1021/jm701257h | |
| dc.identifier.issn | 0022-2623 | |
| dc.identifier.uri | http://hdl.handle.net/10451/21668 | |
| dc.language.iso | eng | |
| dc.publisher | AMER CHEMICAL SOC | |
| dc.subject | Chemistry, Medicinal | |
| dc.title | Azetidine-2,4-diones (4-oxo-beta-lactams) as scaffolds for designing elastase inhibitors | |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.citation.endPage | 1790 | por |
| oaire.citation.startPage | 1783 | por |
| oaire.citation.title | JOURNAL OF MEDICINAL CHEMISTRY | por |
| oaire.citation.volume | Vol. 51 | por |
| rcaap.rights | restrictedAccess | |
| rcaap.type | article |