Stereoselective Inhibition of Cholesterol Esterase by Enantiomers of exo- and endo-2-Norbornyl-N–n-butylcarbamates

Abstract

Four stereoisomers of 2-norbornyl-N-n-butylcarbamates are characterized as the pseudo substrate inhibitors of cholesterol esterase. Cholesterol esterase shows enantioselective inhibition for enantiomers of exo- and endo-2-norbornyl-N-n-butylcarbamates. For the inhibitions by (R)-(+)- and (S)-(-)-exo-2-norbornyl-N-n-butylcarbamates, the R-enantiomer is 6.8 times more potent than the S-enantiomer. For the inhibitions by (R)-(+)- and (S)-(-)-endo-2-norbornyl-N-n-butyl-carbamates, the S-enantiomer is 4.6 times more potent than the R-enantiomer. The enzyme-inhibitor complex models have been proposed to explain these different enantioselectivities.

Climate Change Litigation in India and Pakistan: Analyzing Opportunities and Challenges

“…Commentators have identified Pakistan and India as jurisdictions with strong potential for future climate litigation, based on a history of progressive judgements that have borne from public-interest litigation. 18 Rajamani and Ghosh state that India had an 'engaged and proactive civil society, an activist judiciary, a progressive body of enviro-legal jurisprudence and an unparalleled culture of public interest litigation' that meant it was ripe for climate litigation. 19 Similarly, Lin states that it is 'perhaps just a matter of time before climate change becomes a subject of litigation in the Indian courts'.…”

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

“…[7,8] Furthermore, plasma CEase may contributet oC HD by converting "larger andl ess atherogenic LDL to smaller and more atherogenic LDL subspecies" [8] and by being involved in the generation of cholesterol crystals in LDL aggregates, which are thought of as ah allmark of atherosclerotic plaques and represent ap ossible source of inflammation. [12][13][14][15][16] Most of the initially developed CEase inhibitor classes contain electrophilic sites that are attacked by the active site serine residue (e.g.,b oronic acids, [17] carbamates, [17][18][19][20][21] phosphoisocoumarines, [22] andt hieno [1,3]oxazin-4ones 29 and 30; [23] Figure 1), whereas recently reported rhodanine [24] and thiazolidinedione [24] inhibitors as well as 2-(1 Hindol-3-yl)-4-phenylquinolines [25] do not appear to modify the catalytic triad (Ser-His-Asp). [12][13][14][15][16] Most of the initially developed CEase inhibitor classes contain electrophilic sites that are attacked by the active site serine residue (e.g.,b oronic acids, [17] carbamates, [17][18][19][20][21] phosphoisocoumarines, [22] andt hieno [1,3]oxazin-4ones 29 and 30; [23] Figure 1), whereas recently reported rhodanine [24] and thiazolidinedione [24] inhibitors as well as 2-(1 Hindol...…”

“…[9][10][11] These resultsa nd furtherf indings from in vitro and in vivo studies led to the hypothesis that CEase inhibitors might lower plasma LDL levels and may thus act as antiatherosclerotic agents. [12][13][14][15][16] Most of the initially developed CEase inhibitor classes contain electrophilic sites that are attacked by the active site serine residue (e.g.,b oronic acids, [17] carbamates, [17][18][19][20][21] phosphoisocoumarines, [22] andt hieno [1,3]oxazin-4ones 29 and 30; [23] Figure 1), whereas recently reported rhodanine [24] and thiazolidinedione [24] inhibitors as well as 2-(1 Hindol-3-yl)-4-phenylquinolines [25] do not appear to modify the catalytic triad (Ser-His-Asp). [26,27] Herein, we present the synthesis and characterization of wphthalimidoalkyl aryl ureas 2 and 21 ( Figure 1) as reversible in-Cholesterol esterase (CEase), as erine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as at arget for inhibitor development.W ei nvestigated recombinant human and murineC Eases with an ew fluorometrica ssay in as tructure-activity relationship study of a small library of w-phthalimidoalkyla ryl ureas.…”