Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE).
The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: boyk@bms.com.
Kenneth M
KM
Boy
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Jason M
JM
Guernon
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Yong-Jin
YJ
Wu
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Yunhui
Y
Zhang
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Joe
J
Shi
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Weixu
W
Zhai
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Shirong
S
Zhu
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Samuel W
SW
Gerritz
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Jeremy H
JH
Toyn
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Jere E
JE
Meredith
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Donna M
DM
Barten
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Catherine R
CR
Burton
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Charles F
CF
Albright
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Andrew C
AC
Good
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
James E
JE
Grace
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Kimberley A
KA
Lentz
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Richard E
RE
Olson
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
John E
JE
Macor
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
Lorin A
LA
Thompson
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018938:Caco-2 Cells; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D020059:Cathepsin E / Q000037:antagonists & inhibitors; D004285:Dogs; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D010434:Pepsin A / Q000037:antagonists & inhibitors; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D006146:Guanidines; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011392:Proline; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D010434:Pepsin A; D020059:Cathepsin E; C509282:Bace1 protein, mouse; D002402:Cathepsin D
Alzheimer’s disease; BACE