title: Acylating agents as enzyme inhibitors and understanding their reactivity for drug design.
abstract: A series of bicyclic trans-fused gamma-lactones and gamma-lactams have been previously described for the inhibition of human neutrophil elastase and as possible development candidates. During the discovery program, it had been assumed that their acylating power was due in part to the inherent strain energy in the bicyclic structure that was released upon ring opening. This is now shown not to be the case, and in fact, these compounds are no more reactive than simple but analogous gamma-lactams and gamma-lactones. The strain energy is not released in the transition state for alkaline hydrolysis or alcoholysis because the reaction proceeds with rate-limiting formation of the tetrahedral intermediate. A reactivity index of k(OH) is proposed as a simple guide to determine the usefulness of a potential inhibitor as an enzyme acylating agent.
authors.affiliation: Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield, HD1 3DH, U.K.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Sykes
authors.forename: Simon J F
authors.initials: SJ
authors.lastname: Macdonald
authors.forename: Michael I
authors.initials: MI
authors.lastname: Page
mesh_terms: D000215:Acylation; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D015195:Drug Design; D006868:Hydrolysis; D007700:Kinetics; D007769:Lactams / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020005:Propanols / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014270:Trifluoroethanol / Q000737:chemistry; D014867:Water; D006845:Hydrocarbons, Fluorinated
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D007769:Lactams; D007783:Lactones; D010196:Pancreatic Elastase; D020005:Propanols; D015842:Serine Proteinase Inhibitors; D014270:Trifluoroethanol; D014867:Water; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated