LY 3000328

LY 3000328

Eli Lilly….INNOVATOR

(3R,4S)-4-(4-fluorobenzamido)-6-(4-(oxetan-3-yl)piperazin-1-yl methylcarbamate

Specific rotation: [α]D25 = 55.19 (c = 10,DMSO).

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
http://pubs.acs.org/doi/full/10.1021/ml500283g

Prabhakar K. Jadhav *,et al

Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/ml500283g

Publication Date (Web): August 27, 2014

Copyright © 2014 American Chemical Society

see

http://pubs.acs.org/doi/suppl/10.1021/ml500283g/suppl_file/ml500283g_si_001.pdf

 http://pubs.acs.org/doi/suppl/10.1021/ml500283g/suppl_file/ml500283g_si_001.pdf

ABDOMINAL AORTIC ANEURYSM
Classification and external resources
CT reconstruction image of an abdominal aortic aneurysm

Abdominal aortic aneurysm (also known as AAA,[1] 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 occurinfrarenally (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 theabdominal cavity, and can lead to death within minutes.[2] 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).[3] 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).[4] Open surgery is sometimes still preferred to EVAR, as EVAR requires long-term surveillance with CT Scans.[5]

There is moderate evidence to support screening in individuals with risk factors for abdominal aortic aneurysms (e.g., males ≥65).

DATA

HPLC purity = 98.6% (tR = 24.2 min) by HPLC method 3. ee = 99.9% (tR = 23.6 min) by Chiral HPLC method 4.

Specific rotation: [α]D25 = +55.19 (c = 10,DMSO).

1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.8 Hz, 1H), 8.01 – 7.90 (m, 2H), 7.34 –
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).

13C NMR (DMSO-d6, 100 MHz): δ 165.4, 164.5 (d, J = 248.7 Hz), 156.1, 148.2, 146.2, 131.0, 130.8 (d, J =
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,
47.7, 27.4.

HRMS (ESI+): calcd. for C25H30FN4O5 (M+1): 485.2195, found 485.2188.

1H nmr LY3000328

13 C nmr LY3000328

 

1. Logan, Carolynn M.; Rice, M. Katherine (1987). Logan’s Medical and Scientific Abbreviations. Philadelphia: J. B. Lippincott Company. p. 3.ISBN 0-397-54589-4.
2.  Upchurch GR, Schaub TA (2006). “Abdominal aortic aneurysm”. Am Fam Physician 73(7): 1198–204. PMID 16623206.
3.  Chadi SA et al (2012). “Trends in management of abdominal aortic aneurysms”. J Vasc Surg 55 (4): 924–8. doi:10.1016/j.jvs.2011.10.094.PMID 22226189.
4.  Lederle FA, Freishlag JA et al (209). “Outcomes Following Endovascular vs Open Repair of Abdominal Aortic Aneurysm: A Randomized Trial”.JAMA 302 (14): 1535–42.doi:10.1001/jama.2009.1426. PMID 19826022.
5.  Kirkpatrick VE et al (Dec 2013). “Surveillance Computed Tomographic Arteriogram (CTA) Does Not Change Management before Three Years in Patients Who Have a Normal Post-EVAR Study”. Ann Vasc Surg 28 (4): 831–6. doi:10.1016/j.avsg.2013.09.017.PMID 24361383

Keywords:

Cathepsin, abdominal aortic aneurysm, development candidate, noncovalent, Cathepsin S Inhibitor,  LY3000328,