Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25.
On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5(LY3000328) was selected for clinical development.
Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm
|Abdominal aortic aneurysm|
|Classification and external resources|
CT reconstruction image of an abdominal aortic aneurysm
Abdominal aortic aneurysm (also known as AAA, pronounced “triple-a”) is a localized dilatation (ballooning) of the abdominal aortaexceeding the normal diameter by more than 50 percent, and is the most common form of aortic aneurysm. Approximately 90 percent of abdominal aortic aneurysms occur infrarenally (below the kidneys), but they can also occur pararenally (at the level of the kidneys) orsuprarenally (above the kidneys). Such aneurysms can extend to include one or both of the iliac arteries in the pelvis.
Abdominal aortic aneurysms occur most commonly in individuals between 65 and 75 years old and are more common among men and smokers. They tend to cause no symptoms, although occasionally they cause pain in the abdomen and back (due to pressure on surrounding tissues) or in the legs (due to disturbed blood flow). The major complication of abdominal aortic aneurysms is rupture, which is life-threatening, as large amounts of blood spill into the abdominal cavity, and can lead to death within minutes. Mortality of rupture repair in the hospital is 60% to 90%.
Treatment is usually recommended when an AAA grows to >5.5 cm in diameter. While in the past the only option for the treatment of AAA was open surgery, today most are treated with Endovascular Aneurysm Repair (EVAR). EVAR has been widely adopted, as EVAR has a lower risk of death associated with surgery (0.5% for EVAR vs 3% for open surgery). Open surgery is sometimes still preferred to EVAR, as EVAR requires long-term surveillance with CT Scans.
There is moderate evidence to support screening in individuals with risk factors for abdominal aortic aneurysms (e.g., males ≥65).
7.23 (m, 2H), 7.19 (q, J = 4.5 Hz, 1H), 6.87 (dd, J = 9.0, 2.9 Hz, 1H), 6.78 – 6.69 (m, 2H), 5.03
(dd, J = 8.1, 3.7 Hz, 1H), 4.86 (td, J = 4.1, 1.8 Hz, 1H), 4.52 (t, J = 6.5 Hz, 2H), 4.41 (t, J = 6.0
Hz, 2H), 4.23 (dd, J = 11.8, 1.9 Hz, 1H), 4.13 (ddd, J = 11.8, 4.4, 1.6 Hz, 1H), 3.39 (p, J = 6.3
Hz, 1H), 2.96 (t, J = 4.9 Hz, 4H), 2.52 (d, J = 4.5 Hz, 3H), 2.34 (t, J = 4.9 Hz, 4H).
9.5 Hz), 120.9, 118.6, 117.6, 117.2, 115.6 (d, J = 21.3 Hz), 74.8, 68.7, 64.3, 58.9, 49.8, 49.5,
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