A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose

被引：15

作者：

Durham, Timothy B. ^{[1
]}

Marimuthu, Jothirajah ^{[1
]}

Toth, James L. ^{[1
]}

Liu, Chin ^{[1
]}

Adams, Lisa ^{[1
]}

Mudra, Daniel R. ^{[1
]}

Swearingen, Craig ^{[1
]}

Lin, Chaohua ^{[1
]}

Chambers, Mark G. ^{[1
]}

Thirunavukkarasu, Kannan ^{[1
]}

Wiley, Michael R. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 13期

关键词：

HUMAN SYNOVIAL-FLUID; LIBRARY TECHNOLOGY ELT; CARTILAGE DEGRADATION; INTERGLOBULAR DOMAIN; OSTEOARTHRITIS; FRAGMENTS; DISCOVERY; ADAMTS5; POTENT; DISEASE;

D O I：

10.1021/acs.jmedchem.7b00650

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels >= 10 times the hADAMTS-5 IC50 is 5 mg q.d.

引用

页码：5933 / 5939

页数：7

共 28 条

[1]

Bakali J. E., 2014, FUTURE MED CHEM, V6, P1399

[2]

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis [J].

Dancevic, Carolyn M. ;

McCulloch, Daniel R. .

ARTHRITIS RESEARCH & THERAPY, 2014, 16 (05)

[3]

Discovery of Highly Potent and Selective Small Molecule ADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT) [J].

Deng, Hongfeng ;

O'Keefe, Heather ;

Davie, Christopher P. ;

Lind, Kenneth E. ;

Acharya, Raksha A. ;

Franklin, G. Joseph ;

Larkin, Jonathan ;

Matico, Rosalie ;

Neeb, Michael ;

Thompson, Monique M. ;

Lohr, Thomas ;

Gross, Jeffrey W. ;

Centrella, Paolo A. ;

O'Donovan, Gary K. ;

Bedard, Katie L. ;

van Vloten, Kurt ;

Mataruse, Sibongile ;

Skinner, Steven R. ;

Belyanskaya, Svetlana L. ;

Carpenter, Tiffany Y. ;

Shearer, Todd W. ;

Clark, Matthew A. ;

Cuozzo, John W. ;

Arico-Muendel, Christopher C. ;

Morgan, Barry A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (16) :7061-7079

[4]

Dhanaraj V, 1999, CROAT CHEM ACTA, V72, P575

[5]

Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT) [J].

Ding, Yun ;

O'Keefe, Heather ;

DeLorey, Jennifer L. ;

Israebt, David I. ;

Messer, Jeffrey A. ;

Chiu, Cynthia H. ;

Skinner, Steven R. ;

Matico, Rosalie E. ;

Murray-Thompson, Monique F. ;

Li, Fan ;

Clark, Matthew A. ;

Cuozzo, John W. ;

Arico-Muendel, Christopher ;

Morgan, Barry A. .

ACS MEDICINAL CHEMISTRY LETTERS, 2015, 6 (08) :888-893

[6]

Durham T. B, 2014, W02014/66151, Patent No. [201466151, WO2014066151 A1]

[7]

Identification of Potent and Selective Hydantoin Inhibitors of Aggrecanase-1 and Aggrecanase-2 That Are Efficacious in Both Chemical and Surgical Models of Osteoarthritis [J].

Durham, Timothy B. ;

Klimkowski, Valentine J. ;

Rito, Christopher J. ;

Marimuthu, Jothirajah ;

Toth, James L. ;

Liu, Chin ;

Durbin, Jim D. ;

Stout, Stephanie L. ;

Adams, Lisa ;

Swearingen, Craig ;

Lin, Chaohua ;

Chambers, Mark G. ;

Thirunavukkarasu, Kannan ;

Wiley, Michael R. .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (24) :10476-10485

[8]

Advances in the development of novel aggrecanase inhibitors [J].

Gilbert, Adam M. ;

Bikker, Jack A. ;

O'Neil, Steven V. .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2011, 21 (01) :1-12

[9]

Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice [J].

Glasson, SS ;

Askew, R ;

Sheppard, B ;

Carito, BA ;

Blanchet, T ;

Ma, HL ;

Flannery, CR ;

Kanki, K ;

Wang, E ;

Peluso, D ;

Yang, ZY ;

Majumdar, MK ;

Morris, EA .

ARTHRITIS AND RHEUMATISM, 2004, 50 (08) :2547-2558

[10]

Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis [J].