PMID- 1525156
OWN - NLM
STAT- MEDLINE
DCOM- 19921016
LR  - 20190613
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 31
IP  - 35
DP  - 1992 Sep 8
TI  - Specificity, stability, and potency of monocyclic beta-lactam inhibitors of human 
      leucocyte elastase.
PG  - 8160-70
AB  - Stable, potent, highly specific, time-dependent monocyclic beta-lactam inhibitors 
      of human leucocyte elastase (HLE) are described. The heavily substituted 
      beta-lactams are stable under physiological conditions including in the presence 
      of enzymes of the digestive tract. The beta-lactams were unstable in base. At pH 
      11.3 and 37 degrees C they were hydrolyzed with half-lives of 1.5-2 h. Hydrolysis 
      produced characteristic products including the substituent originally at C-4 of 
      the lactam ring, a substituted urea, and products resulting from decarboxylation 
      of the acid after ring opening. The most potent beta-lactam displayed only 2-fold 
      less activity versus HLE than alpha 1PI, the natural proteinaceous inhibitor. The 
      compounds were more potent against the human and primate PMN elastases than 
      versus either the dog or rat enzymes. Differences in the structure-activity 
      relationships of the human versus the rat enzymes suggest significant differences 
      between these two functionally similar enzymes. The specificity of these 
      compounds toward HLE versus porcine pancreatic elastase (PPE) is consistent with 
      the differences in substrate specificity reported for these enzymes [Zimmerman & 
      Ashe (1977) Biochim. Biophys. Acta 480, 241-245]. These differences suggest that 
      the alkyl substitutions at C-3 of the lactam ring bind in the S1 specificity 
      pocket of these enzymes. The dependence of the stereochemistry at C-4 suggests 
      additional differences between HLE and PPE. Most of the compounds do not inhibit 
      other esterases or human proteases. Weak, time-dependent inhibition of human 
      cathepsin G and alpha-chymotrypsin by one compound suggested a binding mode to 
      these enzymes that places the N-1 substitution in the S1 pocket.
FAU - Knight, W B
AU  - Knight WB
AD  - Department of Enzymology, Medicinal Chemistry Research, Merck Sharp & Dohme 
      Research Laboratory, Rahway, New Jersey 07065.
FAU - Green, B G
AU  - Green BG
FAU - Chabin, R M
AU  - Chabin RM
FAU - Gale, P
AU  - Gale P
FAU - Maycock, A L
AU  - Maycock AL
FAU - Weston, H
AU  - Weston H
FAU - Kuo, D W
AU  - Kuo DW
FAU - Westler, W M
AU  - Westler WM
FAU - Dorn, C P
AU  - Dorn CP
FAU - Finke, P E
AU  - Finke PE
AU  - et al.
LA  - eng
GR  - LM04958/LM/NLM NIH HHS/United States
GR  - RR02301/RR/NCRR NIH HHS/United States
GR  - RR02781/RR/NCRR NIH HHS/United States
GR  - etc.
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (beta-Lactams)
RN  - EC 3.4.21.1 (Chymotrypsin)
RN  - EC 3.4.21.36 (Pancreatic Elastase)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/chemistry/*pharmacology
MH  - Chymotrypsin/chemistry
MH  - Drug Stability
MH  - Humans
MH  - Kinetics
MH  - Leukocyte Elastase
MH  - Mathematics
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Neutrophils/enzymology
MH  - Pancreas/enzymology
MH  - Pancreatic Elastase/*antagonists & inhibitors
MH  - Protein Conformation
MH  - Structure-Activity Relationship
MH  - beta-Lactams
EDAT- 1992/09/08 00:00
MHDA- 1992/09/08 00:01
CRDT- 1992/09/08 00:00
PHST- 1992/09/08 00:00 [pubmed]
PHST- 1992/09/08 00:01 [medline]
PHST- 1992/09/08 00:00 [entrez]
AID - 10.1021/bi00150a007 [doi]
PST - ppublish
SO  - Biochemistry. 1992 Sep 8;31(35):8160-70. doi: 10.1021/bi00150a007.