Aortic Binding of AZD5248: Mechanistic Insight and Reactivity Assays To Support Lead Optimzation.
The oral dipeptidyl peptidase 1 (DPP1) inhibitor AZD5248 showed aortic binding in a rat quantitative whole-body autoradiography (QWBA) study, and its development was terminated prior to human dosing. A mechanistic hypothesis for this finding was established invoking reactivity with aldehydes involved in the cross-linking of elastin, a major component of aortic tissue. This was tested by developing a simple aldehyde chemical reactivity assay and a novel in vitro competitive covalent binding assay. Results obtained with AZD5248, literature compounds, and close analogues of AZD5248 support the mechanistic hypothesis and provide validation for the use of these assays in a two tier screening approach to support lead optimization. The strengths and limitations of these assays are discussed.
Global Safety Assessment, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Ryan A
RA
Bragg
Global Safety Assessment, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Simon
S
Brocklehurst
Global Safety Assessment, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Frida
F
Gustafsson
Global Safety Assessment, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
James
J
Goodman
Global Safety Assessment, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Kevin
K
Hickling
DMPK Innovative Medicines, AstraZeneca , Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom.
Philip A
PA
MacFaul
Global Safety Assessment, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Steve
S
Swallow
Global Safety Assessment, AstraZeneca , Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Jonathan
J
Tugwood
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001345:Autoradiography; D001713:Biphenyl Compounds / Q000737:chemistry / Q000378:metabolism*; D020789:Cathepsin C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008854:Microscopy, Electron; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
C000607639:AZD5248; D001713:Biphenyl Compounds; D011480:Protease Inhibitors; D020789:Cathepsin C