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Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm



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 Inline image 1
Abstract Image
LY 3000328
(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

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
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 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.[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).

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
Inline image 2
13 C nmr LY3000328
Inline image 3
  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


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

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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