(T0930-10-59) Interventional Treatment with an mPGES-1 Inhibitor Halts Further Growth of Abdominal Aortic Aneurysms in the Ang-II Mouse Model

Purpose: Abdominal aortic aneurysm (AAA) is a deadly, permanent balloon of the aortic artery. Surgery is the only option available to patients, but it is risky. In addition, there are currently no FDA-approved pharmacological treatments for AAA available. Notably, microsomal prostaglandin E2 synthase-1 (mPGES-1) is recognized as a promising target for development of a next generation of anti-inflammatory drugs. With structure-based rational design, we have previously developed a mPGES-1 inhibitor as a potential anti-inflammatory drug candidate [1, 2]. Most previous mouse studies have utilized a prevention-based approach to test novel AAA therapies. Here we use interventional drug treatment at day 7 to halt further growth of an established AAA to emphasize translatability into the clinical setting. The purpose of this study was to assess the capability of a lead small-molecule mPGES-1 inhibitor (UK4b) to prevent further growth of AAA in the angiotensin (Ang)-II induced mouse model [1,2].

Methods: For 28 days, three groups of male ApoE-/- mice were infused with Ang-II (1,000 ng/kg/min). Starting on day 7, mice were administered UK4b (drug) 10 mg/kg SC bid (N = 6), UK4b 20 mg/kg SC bid (N = 7), or no drug (control group, N = 14). Maximal aortic diameter was measured by ultrasound on day 0 (baseline), 2, 5, 7, 14, 21, 28 and ex vivo on day 28. Independently, serum UK4b levels were measured by HPLC in wild-type mice to assess PK parameters at 10 mg/kg SC.

Results: On day 28, there was a significant difference in in vivo maximal aortic diameter between each intervention group and the control group (p = 0.0107 and p = 0.0069). AAA formation was seen at day 7 in all groups (diameter ≥ 1.2 mm). There was no statistically significant increase in aortic diameter from day 7 to day 28 in either drug intervention group (p ≥ 0.8) while continued dilation was observed in the control group (p = 0.0305). Serum levels of UK4b indicated C_max = 3.1 ± 1.44 µM and T_max = 1.5 hours post-administration (10 mg/kg SC).

Conclusion: In summary, the mPGES-1 inhibitor UK4b was able to prevent further progression of AAA at two doses in Ang-II infused ApoE-/- mice. There was no significant change in maximal aortic diameter in the treatment groups after intervention at day 7 while the control group experienced significant further dilation. Together, these results show promise for the use of a mPGES-1 inhibitor in the interventional treatment of AAA.

References: [1] Ding K, Zhou Z, Hou S, Yuan Y, Zhou S, Zheng X, Chen J, et al. Structure-based discovery of mPGES-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of anti-inflammatory drugs. Sci Rep. 2018; 8:5205.
[2] Weaver LM, Stewart MJ, Ding K, Zhou S, Loftin C, Zheng F, Zhan C-G. An mPGES-1 Inhibitor Halts Abdominal Aortic Aneurysm Formation in Mice. Circulation. 2021;144:A13612.