Discovery and SAR of spirochromane Akt inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 8, 2011, Pages 2410-2414

  Kallan, Nicholas C ^a   Spencer, Keith L ^a   Blake, James F ^a   Xu, Rui ^a   Heizer, Justin ^a   Bencsik, Josef R ^a   Mitchell, Ian S ^a   Gloor, Susan L ^a   Martinson, Matthew ^a   Risom, Tyler ^a   Gross, Stefan D ^a   Morales, Tony H ^a   Wu, Wen I ^a   Vigers, Guy P A ^a   Brandhuber, Barbara J ^a   Skelton, Nicholas J ^b  

^a ARRAY BIOPHARMA INC   (United States)

^b GENENTECH INC   (United States)

Author keywords

Akt kinase inhibitors

Indexed keywords

PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR;

ANIMAL CELL; ARTICLE; CELL STRAIN LNCAP; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG POTENCY; DRUG SELECTIVITY; ENZYME INHIBITION; FRIEDEL CRAFTS REACTION; HIGH THROUGHPUT SCREENING; IC 50; NONHUMAN; STRUCTURE ACTIVITY RELATION;

BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG EVALUATION, PRECLINICAL; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79953291900     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.02.073     Document Type: Article

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17. For all of the analogs described herein, the Akt2 and Akt3 potencies followed similar trends to Akt1 potency, albeit with activities ca. 5- to 10-fold less potent.
18. Potencies in the Akt1 enzyme assay as well as the phosphorylation of PRAS40 in LNCaP cells were measured as described in Ref. 5a.
19. The relative configurations at the spiropiperidine stereocenters of 7-d1 and 7-d2 were not determined.
20. Generated as outlined in Scheme 1 using ethoxyethylamine, 2,6-dimethylphenylsulfonyl chloride, and (R)-epichlorohydrin.
21. An inseparable mixture of the Boc-deprotected styrene and fully reduced core were formed during step (a) (iii) in Scheme 3. Thus, Boc reprotection and hydrogenation were required to provide spirochromane intermediate 31 cleanly.