Orally active .beta.-lactam inhibitors of human leukocyte elastase-1. Activity of 3,3-diethyl-2-azetidinones

Shah, Shrenik K.; Dorn, Conrad P.; Finke, Paul E.; Hale, Jeffrey J.; Hagmann, William K.; Brause, Karen A.; Chandler, Gilbert O.; Kissinger, Amy L.; Ashe, Bonnie M.

doi:10.1021/jm00099a003

Cited by 69 publications

(20 citation statements)

References 2 publications

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“…Previously it had been reported that the addition of substituents to the C-3 position of other monobactam inhibitors gave improvements in inhibitory activity, stability, and selectivity. , Substitutions at this position were therefore explored with the aim of improving both the potency and the stability profile of our compounds (Table ). The addition of a methyl group cis to the C-4 benzyl group ( 31 ) resulted in a 6-fold drop in inhibitor activity, while the corresponding trans isomer 32 was equipotent with compound 30 (entries 1−3).…”

Section: Resultsmentioning

confidence: 99%

β-Lactam Derivatives as Inhibitors of Human Cytomegalovirus Protease

et al. 1998

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The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the beta-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.

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Section: Resultsmentioning

confidence: 99%

β-Lactam Derivatives as Inhibitors of Human Cytomegalovirus Protease

et al. 1998

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“…(ii) The second type of inhibition may be reversible concerning the enzyme but in such case the inhibitor is definitively altered. hydroxysuccinimide [100] or β-lactams [101] are considered as more potent HNE inhibitors. The above-mentioned functions undergo ring opening by the hydroxyl group of Ser195 to afford an acyl-enzyme, followed by elimination of a conveniently attached leaving group (LG).…”

Section: Design Of Dual Neutrophil Elastase / Mmp Inhibitorsmentioning

confidence: 99%

Neutrophil Elastase as a Target in Lung Cancer

Moroy¹,

Alix

Sápi³

et al. 2012

ACAMC

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Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis. Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named "LipoGalardin" (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.

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“…Mechanism-based inhibitors possess an electrophilic carbonyl that is attacked by Ser-195, forming an intermediate acyl-enzyme which unmasks a previously concealed functional group that can further react covalently at the active site. This class includes isocoumarins, , sulfonyloxy succinimides and phthalimides, − and cephem sulfones and monocyclic β-lactams, − as well as benzisothiazolones. , …”

Section: Introductionmentioning

confidence: 99%

Novel Thieno[2,3-d][1,3]oxazin-4-ones as Inhibitors of Human Leukocyte Elastase

Gütschow

Neumann

1998

J. Med. Chem.

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A series of thieno[2,3-d][1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase. New synthetic routes to 2-alkoxy-, 2-alkylthio-, and 2-sec-amino-substituted derivatives are reported. This study demonstrates the versatility of 2-aminothiophenes prepared by Gewald reaction as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazin-4-ones. Introduction of ethoxy, n-propoxy, and ethylthio groups at C-2 delivered the most potent inhibitors of this series with Ki values lower than 11 nM. Kinetic studies and product analyses revealed the formation of acyl-enzymes as a result of the attack of the active site serine at the carbon C-4 and subsequent deacylation. This mode of action is similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. Replacement of the benzene ring in benzoxazinones by a (substituted) thiophene led to improved hydrolytic stability and retained inhibitory potency.

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Orally active .beta.-lactam inhibitors of human leukocyte elastase-1. Activity of 3,3-diethyl-2-azetidinones

Cited by 69 publications

References 2 publications

β-Lactam Derivatives as Inhibitors of Human Cytomegalovirus Protease

β-Lactam Derivatives as Inhibitors of Human Cytomegalovirus Protease

Neutrophil Elastase as a Target in Lung Cancer

Novel Thieno[2,3-d][1,3]oxazin-4-ones as Inhibitors of Human Leukocyte Elastase

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