Conformationally biased P3 amide replacements of beta-secretase inhibitors.
We have synthesized and evaluated a series of conformationally biased P3 amide replacements based on an isophthalamide lead structure. The studies resulted in the identification of the beta-secretase inhibitor 7m which has an in vitro IC(50)=35 nM. The synthesis and biological activities of these compounds are described.
Stachel
Shawn J
SJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shawn_stachel@merck.com
Coburn
Craig A
CA
Steele
Thomas G
TG
Crouthamel
Min-Chi
MC
Pietrak
Beth L
BL
Lai
Ming-Tain
MT
Holloway
M Katharine
MK
Munshi
Sanjeev K
SK
Graham
Samuel L
SL
Vacca
Joseph P
JP
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010795:Phthalic Acids / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D010795:Phthalic Acids; D011480:Protease Inhibitors; C059768:isophthalate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases