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)

Journal of Medicinal Chemistry

Volumn 59, Issue 10, 2016, Pages 4859-4866

  Degorce, Sébastien L ^a   Boyd, Scott ^a   Curwen, Jon O ^a   Ducray, Richard ^a   Halsall, Christopher T ^a   Jones, Clifford D ^a   Lach, Franck ^a   Lenz, Eva M ^a   Pass, Martin ^a   Pass, Sarah ^a   Trigwell, Catherine ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AZD 9362; PHOSPHOTRANSFERASE INHIBITOR; UNCLASSIFIED DRUG; AZD9362; PROTEIN KINASE INHIBITOR; PYRAZOLE DERIVATIVE; PYRIDINE DERIVATIVE; SOMATOMEDIN C RECEPTOR;

ARTICLE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG SYNTHESIS; HUMAN; IN VITRO STUDY; NONHUMAN; PROTEIN BINDING; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; FEMALE; METABOLISM; MOLECULAR MODEL; MOUSE; NUDE MOUSE; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; FEMALE; MICE; MICE, NUDE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PYRAZOLES; PYRIDINES; RECEPTOR, IGF TYPE 1; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84971665242     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00203     Document Type: Article

References (16)

1. Rochester, M. A.; Riedemann, J.; Hellawell, G. O.; Brewster, S. F.; Macaulay, V. M. Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer Cancer Gene Ther. 2005, 12, 90-100 10.1038/sj.cgt.7700775
2. Zha, J.; Lackner, M. R. Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy Clin. Cancer Res. 2010, 16, 2512-2517 10.1158/1078-0432.CCR-09-2232
3. Mulvihill, M. J.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.; Foreman, K.; Landfair, D.; O'Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.; Arnold, L. D.; Gibson, N. W.; Ji, Q. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor Future Med. Chem. 2009, 1, 1153-1171 10.4155/fmc.09.89
4. Wittman, M. D.; Carboni, J. M.; Yang, Z.; Lee, F. Y.; Antman, M.; Attar, R.; Balimane, P.; Chang, C.; Chen, C.; Discenza, L.; Frennesson, D.; Gottardis, M. M.; Greer, A.; Hurlburt, W.; Johnson, W.; Langley, D. R.; Li, A.; Li, J.; Liu, P.; Mastalerz, H.; Mathur, A.; Menard, K.; Patel, K.; Sack, J.; Sang, X.; Saulnier, M.; Smith, D.; Stefanski, K.; Trainor, G.; Velaparthi, U.; Zhang, G.; Zimmermann, K.; Vyas, D. M. Discovery of a 2,4-disubstituted pyrrolo1,2-f]1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development J. Med. Chem. 2009, 52, 7360-7363 10.1021/jm900786r
5. Ducray, R.; Simpson, I.; Jung, F. H.; Nissink, J. W.; Kenny, P. W.; Fitzek, M.; Walker, G. E.; Ward, L. T.; Hudson, K. Discovery of novel imidazo1,2-a]pyridines as inhibitors of the insulin-like growth factor-1 receptor tyrosine kinase Bioorg. Med. Chem. Lett. 2011, 21, 4698-4701 10.1016/j.bmcl.2011.06.093
6. Ducray, R.; Jones, C. D.; Jung, F. H.; Simpson, I.; Curwen, J.; Pass, M. Novel imidazo1,2-a]pyridine based inhibitors of the IGF-1 receptor tyrosine kinase: Optimization of the aniline Bioorg. Med. Chem. Lett. 2011, 21, 4702-4704 10.1016/j.bmcl.2011.06.090
7. Jones, C. D.; Andrews, D. M.; Barker, A. J.; Blades, K.; Daunt, P.; East, S.; Geh, C.; Graham, M. A.; Johnson, K. M.; Loddick, S. A.; McFarland, H. M.; McGregor, A.; Moss, L.; Rudge, D. A.; Simpson, P. B.; Swain, M. L.; Tam, K. Y.; Tucker, J. A.; Walker, M. The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing Bioorg. Med. Chem. Lett. 2008, 18, 6369-6373 10.1016/j.bmcl.2008.10.102
8. William, A. D.; Lee, A. C.-H.; Blanchard, S.; Poulsen, A.; Teo, E. L.; Nagaraj, H.; Tan, E.; Chen, D.; Williams, M.; Sun, E. T.; Goh, K. C.; Ong, W. C.; Goh, S. K.; Hart, S.; Jayaraman, R.; Pasha, M. K.; Ethirajulu, K.; Wood, J. M.; Dymock, B. W. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma J. Med. Chem. 2011, 54, 4638-4658 10.1021/jm200326p
9. Finlay, M. R.; Anderton, M.; Ashton, S.; Ballard, P.; Bethel, P. A.; Box, M. R.; Bradbury, R. H.; Brown, S. J.; Butterworth, S.; Campbell, A.; Chorley, C.; Colclough, N.; Cross, D. A. E.; Currie, G. S.; Grist, M.; Hassall, L.; Hill, G. B.; James, D.; James, M.; Kemmitt, P.; Klinowska, T.; Lamont, G.; Lamont, S. G.; Martin, N.; McFarland, H. L.; Mellor, M. J.; Orme, J. P.; Perkins, D.; Perkins, P.; Richmond, G.; Smith, P.; Ward, R. A.; Waring, M. J.; Whittaker, D.; Wells, S.; Wrigley, G. L. 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. Med. Chem. 2014, 57, 8249-8267 10.1021/jm500973a
10. Ducray, R.; Jones, C. D.; Jung, F. H.; Simpson, I. Preparation of imidazopyridinyl and pyrazolopyridinyl pyrimidinamines as IGF-1R inhibitors for treating cancer U.S. Pat. Appl. Publ. US20100105655A1, 2010.
11. Hopkins, A. L.; Keserue, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H. The role of ligand efficiency metrics in drug discovery Nat. Rev. Drug Discovery 2014, 13, 105-121 10.1038/nrd4163
12. Malumbres, M.; Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm Nat. Rev. Cancer 2009, 9, 153-166 10.1038/nrc2602
13. Emmitte, K. A.; Wilson, B. J.; Baum, E. W.; Emerson, H. K.; Kuntz, K. W.; Nailor, K. E.; Salovich, J. M.; Smith, S. C.; Cheung, M.; Gerding, R. M.; Stevens, K. L.; Uehling, D. E.; Mook, R. A., Jr.; Moorthy, G. S.; Dickerson, S. H.; Hassell, A. M.; Anthony Leesnitzer, M.; Shewchuk, L. M.; Groy, A.; Rowand, J. L.; Anderson, K.; Atkins, C. L.; Yang, J.; Sabbatini, P.; Kumar, R. Discovery and optimization of imidazo[1,2-a]pyridine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) Bioorg. Med. Chem. Lett. 2009, 19, 1004-1008 10.1016/j.bmcl.2008.11.058
14. Buttar, D.; Colclough, N.; Gerhardt, S.; MacFaul, P. A.; Phillips, S. D.; Plowright, A.; Whittamore, P.; Tam, K.; Maskos, K.; Steinbacher, S.; Steuber, H. A combined spectroscopic and crystallographic approach to probing drug-human serum albumin interactions Bioorg. Med. Chem. 2010, 18, 7486-7496 10.1016/j.bmc.2010.08.052
15. Soars, M. G.; Grime, K.; Sproston, J. L.; Webborn, P. J. H.; Riley, R. J. Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo Drug Metab. Dispos. 2007, 35, 859-865 10.1124/dmd.106.014464
16. Bridgland-Taylor, M. H.; Hargreaves, A. C.; Easter, A.; Orme, A.; Henthorn, D. C.; Ding, M.; Davis, A. M.; Small, B. G.; Heapy, C. G.; Abi-Gerges, N.; Persson, F.; Jacobson, I.; Sullivan, M.; Albertson, N.; Hammond, T. G.; Sullivan, E.; Valentin, J. P.; Pollard, C. E. Optimisation and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks HT J. Pharmacol. Toxicol. Methods 2006, 54, 189-199 10.1016/j.vascn.2006.02.003