Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors.
The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110 nM) demonstrated a reduction in CSF Aβ in wild type rats after a single dose.
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: volgrafm@gene.com.
Matthew
M
Volgraf
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Lina
L
Chan
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Malcolm P
MP
Huestis
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Hans E
HE
Purkey
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Michael
M
Burkard
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Mary
M
Geck Do
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Julie
J
Harris
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Kevin W
KW
Hunt
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Xingrong
X
Liu
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Joseph P
JP
Lyssikatos
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Sumeet
S
Rana
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Allen A
AA
Thomas
Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States.
Guy P A
GP
Vigers
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
Michael
M
Siu
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D008968:Molecular Conformation; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine
C000593989:7'-(5-chloropyridin-3-yl)-3',4',4a',10a'-tetrahydro-1'H,5H-spiro(oxazole-4,5'-pyrano(3,4-b)chromen)-2-amine; D016229:Amyloid beta-Peptides; D001578:Benzopyrans; D010080:Oxazoles; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer’s disease; BACE1 inhibitors; Structure-based ligand design