Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R)

被引：31

作者：

Degorce, Sebastien L. ^{[1
,2
]}

Boyd, Scott ^{[1
]}

Curwen, Jon O. ^{[1
]}

Ducray, Richard ^{[2
]}

Halsall, Christopher T. ^{[1
]}

Jones, Clifford D. ^{[1
,2
]}

Lach, Franck ^{[2
]}

Lenz, Eva M. ^{[1
]}

Pass, Martin ^{[1
]}

Pass, Sarah ^{[1
]}

Trigwell, Catherine ^{[1
]}

机构：

[1] AstraZeneca, Oncol Innovat Med Unit, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Ctr Rech, Oncol Innovat Med Unit, BP1050, F-51689 Reims 2, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 10期

关键词：

WILD-TYPE; OPTIMIZATION;

D O I：

10.1021/acs.jmedchem.6b00203

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：

Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-p-yrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.

引用

页码：4859 / 4866

页数：8

共 16 条

[1]

Bridgland-Taylor M. H., 2006, Journal of Pharmacological and Toxicological Methods, V54, P189, DOI 10.1016/j.vascn.2006.02.003

[2]

A combined spectroscopic and crystallographic approach to probing drug-human serum albumin interactions [J].

Buttar, David ;

Colclough, Nicola ;

Gerhardt, Stefan ;

MacFaul, Philip A. ;

Phillips, Scott D. ;

Plowright, Alleyn ;

Whittamore, Paul ;

Tam, Kin ;

Maskos, Klaus ;

Steinbacher, Stefan ;

Steuber, Holger .

BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (21) :7486-7496

[3]

Ducray R., 2010, U.S. Pat. Appl. Publ., Patent No. [US20100105655A1, 20100105655]

[4]

Novel imidazo[1,2-a]pyridine based inhibitors of the IGF-1 receptor tyrosine kinase: Optimization of the aniline [J].

Ducray, Richard ;

Jones, Clifford D. ;

Jung, Frederic H. ;

Simpson, Iain ;

Curwen, Jon ;

Pass, Martin .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (16) :4702-4704

[5]

Discovery of novel imidazo[1,2-a]pyridines as inhibitors of the insulin-like growth factor-1 receptor tyrosine kinase [J].

Ducray, Richard ;

Simpson, Iain ;

Jung, Frederic H. ;

Nissink, J. Willem M. ;

Kenny, Peter W. ;

Fitzek, Martina ;

Walker, Graeme E. ;

Ward, Lara T. ;

Hudson, Kevin .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (16) :4698-4701

[6]

Discovery and optimization of imidazo[1,2-α]pyridine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) [J].

Emmitte, Kyle A. ;

Wilson, Brian J. ;

Baum, Erich W. ;

Emerson, Holly K. ;

Kuntz, Kevin W. ;

Nailor, Kristen E. ;

Salovich, James M. ;

Smith, Stephon C. ;

Cheung, Mui ;

Gerding, Roseanne M. ;

Stevens, Kirk L. ;

Uehling, David E. ;

Mook, Robert A., Jr. ;

Moorthy, Ganesh S. ;

Dickerson, Scott H. ;

Hassell, Anne M. ;

Leesnitzer, M. Anthony ;

Shewchuk, Lisa M. ;

Groy, Arthur ;

Rowand, Jason L. ;

Anderson, Kelly ;

Atkins, Charity L. ;

Yang, Jingsong ;

Sabbatini, Peter ;

Kumar, Rakesh .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (03) :1004-1008

[7]

Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor [J].

Finlay, M. Raymond V. ;

Anderton, Mark ;

Ashton, Susan ;

Ballard, Peter ;

Bethel, Paul A. ;

Box, Matthew R. ;

Bradbury, Robert H. ;

Brown, Simon J. ;

Butterworth, Sam ;

Campbell, Andrew ;

Chorley, Christopher ;

Colclough, Nicola ;

Cross, Darren A. E. ;

Currie, Gordon S. ;

Grist, Matthew ;

Hassall, Lorraine ;

Hill, George B. ;

James, Daniel ;

James, Michael ;

Kemmitt, Paul ;

Klinowska, Teresa ;

Lamont, Gillian ;

Lamont, Scott G. ;

Martin, Nathaniel ;

McFarland, Heather L. ;

Mellor, Martine J. ;

Orme, Jonathon P. ;

Perkins, David ;

Perkins, Paula ;

Richmond, Graham ;

Smith, Peter ;

Ward, Richard A. ;

Waring, Michael J. ;

Whittaker, David ;

Wells, Stuart ;

Wrigley, Gail L. .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (20) :8249-8267

[8]

The role of ligand efficiency metrics in drug discovery [J].

Hopkins, Andrew L. ;

Keserue, Gyoergy M. ;

Leeson, Paul D. ;

Rees, David C. ;

Reynolds, Charles H. .

NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (02) :105-121

[9]

The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing [J].

Jones, Clifford D. ;

Andrews, David M. ;

Barker, Andrew J. ;

Blades, Kevin ;

Daunt, Paula ;

East, Simon ;

Geh, Catherine ;

Graham, Mark A. ;

Johnson, Keith M. ;

Loddick, Sarah A. ;

McFarland, Heather M. ;

McGregor, Alexandra ;

Moss, Louise ;

Rudge, David A. ;

Simpson, Peter B. ;

Swain, Michael L. ;

Tam, Kin Y. ;

Tucker, Julie A. ;

Walker, Mike .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (24) :6963-6967

[10]

Cell cycle, CDKs and cancer: a changing paradigm [J].

Malumbres, Marcos ;

Barbacid, Mariano .

NATURE REVIEWS CANCER, 2009, 9 (03) :153-166

← 1 2 →