Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1 H-indol-1-yl]pyridine-2-yl}propanoic Acid

• A lead generation campaign identified indole-based sPLA2-X inhibitors with a promising selectivity profile against other sPLA2 isoforms. Further optimization of sPLA2 selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA2-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE-/- murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA2-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.

Ämnesord

TEKNIK OCH TEKNOLOGIER  -- Kemiteknik (hsv//swe)

ENGINEERING AND TECHNOLOGY  -- Chemical Engineering (hsv//eng)

Nyckelord

atherosclerosis

carotid ligation

coronary artery disease

inhibitor

Secreted phospholipase A2 type X

sPLA2-X

2 [2 [carbamoyl 6 (trifluoromethoxy) 1h indol 1 yl]pyridine 2 yl]propanoic Acid

propionic acid derivative

unclassified drug

animal experiment

animal model

Article

carotid artery ligation

controlled study

drug absorption

drug bioavailability

drug clearance

drug design

drug potency

drug selectivity

IC50

IC90

in vitro study

in vivo study

lipophilicity

male

mouse

nonhuman

plasma protein binding

priority journal

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)