Aminothienopyridazine inhibitors of tau aggregation: evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo properties.
Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50mg/kg/day.
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA. bcarlo@sas.upenn.edu
Carlo
C
Ballatore
Alex
A
Crowe
Francesco
F
Piscitelli
Michael
M
James
Kevin
K
Lou
Gabrielle
G
Rossidivito
Yuemang
Y
Yao
John Q
JQ
Trojanowski
Virginia M-Y
VM
Lee
Kurt R
KR
Brunden
Amos B
AB
Smith
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
C575849:5-amino-N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno(3,4-d)pyridazine-1-carboxamide; D003521:Cyclopropanes; D011724:Pyridazines; D016875:tau Proteins; C062482:pyridazine