200P London, UK
Pharmacology 2016



Structure-activity relationship of a novel family of cysteinyl leukotriene receptor antagonist quinoline compounds with anti-angiogenic activity.

A. L. Reynolds1, P. Ventosa2, J. Granander1, C. Kilty1, E. Young1, C. T. Butler1, O. Galvin1, S. Merrigan1, T. Sasore1, Y. Fernandez2, D. Gilheany1, B. N. Kennedy1. 1University College Dublin, Dublin, IRELAND, 2Gadea Pharmaceutical Group, Valladolid, SPAIN.

Introduction: Previously, we identified quininib (2-[(E)-2-(quinolin-2-yl)vinyl]phenol), a cysteinyl leukotriene receptor antagonist with anti-angiogenic and anti-permeable activity (1,2). Here, we report a structure activity relationship study to more comprehensively characterise features which confer anti-angiogenic activity.

Methods: 70 quininib analogues were synthesised or purchased (3). Anti-angiogenic activity was ranked based on ability of 10 µM compound to inhibit blood vessel formation in two in vivo developmental angiogenesis assays in Tg[fli1:EGFP] zebrafish (i) hyaloid/ocular vessel formation and (ii) intersegmental /tail vessel formation. Compounds were considered active where ≥40% inhibition was observed compared to control. Selected highly ranked compounds were tested in human endothelial cell lines (HMEC-1) for cytoxicity (MTT assay) and anti-angiogenic activity (in vitro tubule formation assay). Efficacy was also determined in mouse aortic ring assay (4). CYSLT receptor antagonism was quantified using reporter cell bioassays.

Results: 18 analogues showed ≥40% inhibition in formation of hyaloid vessels and fourteen showed ≥40% inhibition in formation of intersegmental vessels. These compounds comprised those with “triene” bond and benzene ring modifications. Six compounds were selected for further testing (Q8: (E)-2-(2-Quinolin-2-yl-vinyl)benzene-1,4-diol HCl; Q 14: 3-(2-Quinolin-2-yl-ethyl)-phenol HCl; Q 18: 2-[(Z)-2-(Quinolin-2-yl)vinyl]phenol HCl; Q 20: (E)-2-(2-Quinolin-2-yl-propenyl)-phenol HCl; Q 22: 2-Quinolin-2-yl-ylethynyl-phenol HCl and Q 54: 2-(2-(2-Methoxyphenyl)vinyl)quinoline). No compound showed an effect on cell viability. Three compounds (Q 8, Q 18, Q 22) showed ≥40% reduction in in vitro tubule length and Q 18 showed ≥40% reduction in sprout formation in the aortic ring assay. Cell bioassays showed all six compounds inhibited LTD4 induced activation of CYSLT1 (IC50: 1.7 - 6.7 µM) and at 30 µM, four compounds (Q 14, Q 18, Q 20, Q 22) showed ≥50% inhibition of LTC4 induced activation of CYSLT2.

Conclusions: More than 10 compounds showed robust anti-angiogenic activity in both assays. Three quinoline compounds demonstrated anti-angiogenic activity in human cell lines and mouse aortic ring. This study is the first step in identifying a quinoline pharmacophore for antagonism of the CYSLT pathway as a therapeutic target for inhibiting the aberrant pathological angiogenesis occurring in blindness, cancer and arthritis.


1. Galvin O et al., (2016). J Control Release 233, 198-207.

2. Reynolds AL et al., (2016). J Biol Chem 291, 7242-7255.

3. Kennedy BN et al., (2016) USPTO US 9,388,138 B2 (Patent).

4. Baker M et al., (2012) Nat. Protoc 7, 89-104.