Macrocyclic inhibitors of beta-secretase: functional activity in an animal model.
A macrocyclic inhibitor of beta-secretase was designed by covalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improved potency and physical properties when compared to the initial lead structures. More importantly, these macrocyclic inhibitors also displayed in vivo amyloid lowering when dosed in a murine model.
Stachel
Shawn J
SJ
Department of Medicinal Chemistry, Biological Chemistry, Molecular Systems and Structural Biology Merck Research Laboratories, Post Office Box 4, West Point, Pennsylvania 19486, USA. shawn_stachel@merck.com
Coburn
Craig A
CA
Sankaranarayanan
Sethu
S
Price
Eric A
EA
Wu
Guoxin
G
Crouthamel
Michelle
M
Pietrak
Beth L
BL
Huang
Qian
Q
Lineberger
Janet
J
Espeseth
Amy S
AS
Jin
Lixia
L
Ellis
Joan
J
Holloway
M Katharine
MK
Munshi
Sanjeev
S
Allison
Timothy
T
Hazuda
Daria
D
Simon
Adam J
AJ
Graham
Samuel L
SL
Vacca
Joseph P
JP
D000577:Amides / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008968:Molecular Conformation; D010795:Phthalic Acids / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D000577:Amides; D016229:Amyloid beta-Peptides; D047028:Macrocyclic Compounds; D010795:Phthalic Acids; D011480:Protease Inhibitors; C059768:isophthalate; D053829:Amyloid Precursor Protein Secretases