Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity Christoph W. Zapf a,⇑ , Jonathan D. Bloom a , Jamie L. McBean a , Russell G. Dushin a , Thomas Nittoli a , Charles Ingalls a , Alan G. Sutherland a , John P. Sonye a , Clark N. Eid a , Jennifer Golas b , Hao Liu b , Frank Boschelli b , Yongbo Hu c , Erik Vogan d , Jeremy I. Levin a a Medicinal Chemistry, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA b Oncology Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA c Structural Biology & Computational Chemistry, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA d Structural Biology & Computational Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02139, USA article info Article history: Received 12 January 2011 Revised 23 February 2011 Accepted 24 February 2011 Available online 28 February 2011 Keywords: Hsp90 inhibitors Chaperon inhibitors ortho-Aminobenzamides N-terminal ATP-binding site Macrocycles Buchwald–Hartwig cyclization abstract A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure–activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay. Ó 2011 Elsevier Ltd. All rights reserved. Modern cancer chemotherapy generally suffers from the emer- gence of drug resistance. 1,2 The selective silencing of a specific cell signaling pathway by a chemotherapeutic is arguably at the origin of this problem. By up-regulating alternative pathways, tumors are able to adapt to the drug treatment and continue their growth. Tar- geting chaperone proteins offers a promising solution to this tradi- tional chemotherapy dilemma since it allows the simultaneous inhibition of multiple pathways with a single agent. 3,4 The ATP-dependent 90 kDa molecular chaperone Hsp90 has be- come an attractive target for cancer therapy. 5,6 It plays a critical role in maintaining the function of a wide range of client proteins many of which are intimately involved in cancer pathology. 7 Inhi- bition of Hsp90 leads to the destabilization and ultimately degra- dation of the clients which results in the inhibition of cell growth and apoptosis. 8 Different ATP-competitive chemotypes have evolved as potent N-terminal Hsp90 inhibitors, several of which have transitioned into clinical trials. 9–11 While many of these clinical trials focus on Hsp90 inhibitors as single agents for cancer therapy, combination studies with established chemotherapeutics have been designed and were reported recently as well. 12 The first Hsp90 inhibitor reported in the literature was the mac- rocyclic natural product Geldanamycin 1 (Fig. 1) which belongs to the class of the ansamycins. 13 Clinical studies established this com- pound’s unacceptable toxicology profile preventing it from further development. 14 Optimization studies led to the discovery of 17- AAG 2 and 17-DMAG 3 15 which are currently in clinical trials but which are characterized by poor solubility and a narrow therapeu- tic window, respectively. Vernalis recently disclosed resorcinol 4 16 which entered clinical trials in 2007. Isoxazole 4 is one of many small molecules which have been described in the literature as potential novel Hsp90 inhibitors with clinical application and is part of a recent summary on this topic. 17 Serenex (acquired by Pfizer) recently disclosed their own efforts to discover potent small-molecule Hsp90 inhibitors that would be devoid of drawbacks associated with Geldanamycin. 18 Their stud- ies culminated in a series of 2-aminobenzamides which exhibited low-nanomolar potencies in a proliferation assay. Among the re- ported compounds, glycine pro-drug SNX-5422 5 was forwarded to clinical trials. 19 Using structure-based drug design, a series of potent benzisox- azoles as Hsp90 inhibitors was recently discovered. 20 In continua- tion of seeking potent small molecule inhibitors of Hsp90 and guided by X-ray crystallography using a structural analog of 5, 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.02.101 ⇑ Corresponding author. Tel.: +1 617 665 5602; fax: +1 617 665 5682. E-mail address: christoph.zapf@pfizer.com (C.W. Zapf). Bioorganic & Medicinal Chemistry Letters 21 (2011) 2278–2282 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl