Design of 7-amino-6-chloro-3H-imidazo[4,5-b]pyridine scaffold from 5-chloro-2,4-diaminopyrimidine pharmacophore: identification of potent inhibitors of anaplastic lymphoma kinase

A series of potent anaplastic lymphoma kinase (ALK) inhibitors based on a 7-amino-6-chloro-3H-imidazo[4,5-b]pyridine scaffold were identified through rational design from a 5-chloro-2,4-diaminopyrimidine pharmacophore, maintaining key binding elements, favourable lipophilic interactions and orienting the side chains into favoured trajectories. Importantly, potency and selectivity determinants from the parent series were directly applicable to the new scaffold. This highly focused strategy led to the identification of several lead inhibitors that displayed potent activity in enzyme and cellular assays as well as pronounced oral bioavailability.

[1]  H. Sakamoto,et al.  Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). , 2012, Bioorganic & medicinal chemistry.

[2]  A. Ghose,et al.  Design, synthesis, and anaplastic lymphoma kinase (ALK) inhibitory activity for a novel series of 2,4,8,22-tetraazatetracyclo[14.3.1.1³,⁷.1⁹,¹³]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene macrocycles. , 2012, Journal of medicinal chemistry.

[3]  D. Gingrich,et al.  Development and Scale-Up of an Optimized Route to the ALK Inhibitor CEP-28122 , 2012 .

[4]  G. Inghirami,et al.  CEP-28122, a Highly Potent and Selective Orally Active Inhibitor of Anaplastic Lymphoma Kinase with Antitumor Activity in Experimental Models of Human Cancers , 2011, Molecular Cancer Therapeutics.

[5]  M. Yazdanian,et al.  2,7-Disubstituted-pyrrolotriazine kinase inhibitors with an unusually high degree of reactive metabolite formation. , 2011, Chemical research in toxicology.

[6]  A. Ghose,et al.  2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity. , 2011, Journal of medicinal chemistry.

[7]  J. Christensen,et al.  Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). , 2011, Journal of medicinal chemistry.

[8]  Andrew V. Anzalone,et al.  Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity. , 2010, ACS medicinal chemistry letters.

[9]  P. Workman,et al.  Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate. , 2010, Journal of medicinal chemistry.

[10]  G. R. Ott,et al.  Anaplastic lymphoma kinase as a therapeutic target in anaplastic large cell lymphoma, non-small cell lung cancer and neuroblastoma. , 2010, Anti-cancer agents in medicinal chemistry.

[11]  A. Look,et al.  Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy , 2009, Expert review of anticancer therapy.

[12]  J. A. Kumar,et al.  Efficient and Inexpensive Synthesis of Benzimidazoles and Quinoxalines , 2008 .

[13]  Zheng Yang,et al.  Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activ , 2008, Journal of medicinal chemistry.

[14]  Rongshi Li,et al.  Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy , 2008, Medicinal research reviews.

[15]  P. Workman,et al.  Hit generation and exploration: imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases. , 2007, Bioorganic & medicinal chemistry letters.

[16]  W. Yung,et al.  Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo , 2007, Molecular Cancer Therapeutics.

[17]  Peter G. Schultz,et al.  Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK , 2007, Proceedings of the National Academy of Sciences.

[18]  Mindy I. Davis,et al.  A quantitative analysis of kinase inhibitor selectivity , 2008, Nature Biotechnology.