Prolonged stability by cyclization: Macrocyclic phosphino dipeptide isostere inhibitors of beta-secretase (BACE1).
Cyclization of recently reported linear phosphino dipeptide isostere inhibitors of BACE1 via side chain olefin metathesis yielded macrocyclic BACE1 inhibitors. The most potent compound II-P1 (IC(50) of 47nM) and the corresponding linear analog I were tested for serum stability. The approach led to three times prolonged half life serum stability of 44min for the macrocyclic inhibitor II-P1 compared to the linear compound I.
Huber
Timo
T
Center of Integrated Protein Science at the Department Chemie and Institute for Advanced Study, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Manzenrieder
Florian
F
Kuttruff
Christian A
CA
Dorner-Ciossek
Cornelia
C
Kessler
Horst
H
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D013997:Time Factors
D004151:Dipeptides; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human