Cis-Amide isosteric replacement in thienobenzoxepin inhibitors of PI3-kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 23, Issue 3, 2013, Pages 897-901

  Staben, Steven T ^a   Blaquiere, Nicole ^a   Tsui, Vickie ^a   Kolesnikov, Aleksandr ^a   Do, Steven ^a   Bradley, Erin K ^a   Dotson, Jenna ^a   Goldsmith, Richard ^a   Heffron, Timothy P ^a   Lesnick, John ^a   Lewis, Cristina ^a   Murray, Jeremy ^a   Nonomiya, Jim ^a   Olivero, Alan G ^a   Pang, Jodie ^a   Rouge, Lionel ^a   Salphati, Laurent ^a   Wei, Binqing ^a   Wiesmann, Christian ^a   Wu, Ping ^a  

^a GENENTECH INC   (United States)

Author keywords

Isostere; PI3 kinase; Property guided design; Structure based design

Indexed keywords

PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; POLYCYCLIC AROMATIC HYDROCARBON; THIENOBENZOXEPIN DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CHEMICAL MODIFICATION; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG PENETRATION; DRUG POTENCY; DRUG SOLUBILITY; DRUG STABILITY; DRUG STRUCTURE; IC 50; LIPOPHILICITY; NONHUMAN; PHYSICAL CHEMISTRY;

AMIDES; BENZOTHIAZOLES; BENZOXEPINS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; ENZYME ACTIVATION; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; PHOSPHATIDYLINOSITOL 3-KINASES; THIOPHENES;

EID: 84872329670     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.10.121     Document Type: Article

References (17)

1. For articles highlighting the relevance of PI3K/PTEN in oncology please see: J.M. Nuss, A.L. Tsuhako, and N.K. Anand Annu. Rep. Med. Chem. 44 2009 339
2. K.-K. Wong, J.A. Engelman, and L.C. Cantley Curr. Opin. Genet. Dev. 20 2010 87
3. Y. Samuels, Z. Wang, A. Bardelli, N. Silliman, J. Ptak, S. Szabo, H. Yan, A. Gazdar, S.M. Powell, G.J. Riggins, J.K.V. Willson, S. Markowitz, K.W. Kinzler, B. Vogelstein, and V.E. Velculescu Science 304 2004 554
4. N.R. Leslie, and C.P. Downes Biochem. J. 382 2004 1
5. S.T. Staben, M. Siu, R. Goldsmith, A.G. Olivero, S. Do, D.J. Burdick, T.P. Heffron, J. Dotson, D.P. Sutherlin, B.-Y. Zhu, V. Tsui, H. Le, L. Lee, J. Lesnick, C. Lewis, J.M. Murray, J. Nonomiya, J. Pang, W.W. Prior, L. Salphati, L. Rouge, D. Sampath, S. Sideris, C. Wiesmann, and P. Wu Bioorg. Med. Chem. Lett. 21 2011 4054
6. T.P. Heffron, B. Wei, A. Olivero, S.T. Staben, V. Tsui, S. Do, J. Dotson, A.J. Folkes, P. Goldsmith, R. Goldsmith, J. Gunzner, J. Lesnick, C. Lewis, S. Mathieu, J. Nonomiya, S. Shuttleworth, D.P. Sutherlin, N.-C. Wan, S. Wang, C. Wiesmann, and B.-Y. Zhu J. Med. Chem. 54 2011 7815
7. For leading references see: B.K. Park, A. Boobis, S. Clarke, C.E.P. Goldring, D. Jones, J.G. Kenna, C. Lambert, H.G. Laverty, D.J. Naisbitt, S. Nelson, D.A. Nicoll-Griffith, R.S. Obach, P. Routledge, D.A. Smith, D.J. Tweedie, N. Vermeulen, D.P. Williams, I.D. Wilson, and T.A. Baillie Nat. Rev. Drug Discovery 10 2011 292
8. Toxicity and covalent binding of 2-chloroaniline has been examined in rats: L.D. Dial, D.K. Anestis, S.R. Kennedy, and G.O. Rankin Toxicology 131 1998 109
9. For discussion of the preferred cis-orientation in solid-state structures of N-methylaniline amides see A. Itai, Y. Toriumi, S. Saito, H. Kagechika, and K. Shudo J. Am. Chem. Soc. 114 1992 10649
10. Y. Toriumi, A. Kasuya, and A. Itai J.Org. Chem. 55 1990 259
11. H. Kagechika, T. Himi, E. Kawachi, and K. Shudo J. Med. Chem. 32 1989 2292 and references therein
12. For a discussion of carbonyl-sulfur interactions restricting small molecule confirmation, see: K.A. Brameld, B. Kuhn, D.C. Reuter, and M. Stahl J. Chem. Inf. Model 48 2008 1
13. Isosterism of a trans-amide is more common N.A. Meanwell J. Med. Chem. 54 2011 2529 and references within
14. D.P. Sutherlin, L. Bao, M. Berry, G. Castanedo, I. Chuckowree, J. Dotson, A. Folks, L. Friedman, R. Goldsmith, J. Gunzner, T.P. Heffron, J. Lesnick, C. Lewis, S. Mathieu, J.M. Murray, J. Nonomiya, J. Pang, N. Pegg, W.W. Prior, L. Rouge, L. Salphati, D. Sampath, Q. Tian, V. Tsui, N.-C. Wan, S. Wang, B.-Q. Wei, C. Wiesmann, P. Wu, B.-Y. Zhu, and A. Olivero J. Med. Chem. 54 2011 7579
15. Recent other PI3K inhibitors have been disclosed with an N-H-1,2,4-triazole in the affinity pocket as result of isosterism of a primary amide: K.-C. Liu, J. Zhu, G.L. Smith, M.-J. Yin, S. Bailey, J.H. Chen, Q. Hu, Q. Huang, C. Li, Q.J. Li, M.A. Marx, G. Paderes, P.F. Richardson, N.W. Sach, M. Walls, P.A. Wells, and A. Zou ACS Med. Chem. Lett. 2 2011 809
16. A.P. Hill, and R.J. Young Drug Discovery Today 15 2010 648 The authors recommend a solubility forcast index (c Log D7.4+ # of aromatic rings) of <7 to improve probability of high kinetic solubility.
17. The synthesis of all analogs in this manuscript have been described in the following patent application: Do, S.; Goldsmith, R.; Heffron, T.; Kolesnikov, A.; Staben, S.; Olivero, A.; Siu, M.; Sutherlin, D. P.; Zhu, B. -Y.; Goldsmith, P.; Bayliss, T.; Folkes, A.; Pegg, N. WO/2009/123971; U.S. 7928,248.