A conformational constraint improves a beta-secretase inhibitor but for an unexpected reason.
During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.
Hills
Ivory D
ID
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., West Point, PA 19486, USA. ivory_hills@merck.com
Holloway
M Katharine
MK
de León
Pablo
P
Nomland
Ashley
A
Zhu
Hong
H
Rajapakse
Hemaka
H
Allison
Tim J
TJ
Munshi
Sanjeev K
SK
Colussi
Dennis
D
Pietrak
Beth L
BL
Toolan
Dawn
D
Haugabook
Sharie J
SJ
Graham
Samuel L
SL
Stachel
Shawn J
SJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007093:Imidazoles; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases