Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt

Bioorganic and Medicinal Chemistry

Volumn 15, Issue 6, 2007, Pages 2441-2452

  Zhu, Gui Dong ^a   Gong, Jianchun ^a   Gandhi, Viraj B ^a   Woods, Keith ^a   Luo, Yan ^a   Liu, Xuesong ^a   Guan, Ran ^a   Klinghofer, Vered ^a   Johnson, Eric F ^a   Stoll, Vincent S ^a   Mamo, Mulugeta ^a   Li, Qun ^a   Rosenberg, Saul H ^a   Giranda, Vincent L ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

Akt inhibitor; Protein kinase B; Pyrazolopyridine; Serine threonine kinase

Indexed keywords

1 (1H INDOL 3 YL) 3 [5 (3 METHYL 1H PYRAZOLO[3,4 C]PYRIDIN 5 YL)PYRIDIN 3 YLOXY] PROPAN 2 AMINE; 1 (1H INDOL 3 YL) 3 [5 (6 AMINO 1H INDAZOL 5 YL)PYRIDIN 3 YLOXY]PROPAN 2 AMINE; 1 (1H INDOL 3 YL) 3 [5 (6 NITRO 1H INDAZOL 5 YL)PYRIDIN 3 YLOXY]PROPAN 2 AMINE; 1 [5 (1H PYRAZOLO[3,4 C]PYRIDIN 5 YL)PYRIDIN 3 YLOXY] 3 (1H INDOL 3 YL)PROPAN 2 AMINE; 1 [5 (1H PYRAZOLO[3,4 C]PYRIDIN 5 YL)PYRIDIN 3 YLOXY] 3 PHENYLPROPAN 2 AMINE; 1 [5 (3 CHLORO 1H INDAZOL 5 YL)PYRIDIN 3 YLOXY] 3 (1H INDOL 3 YL)PROPAN 2 AMINE; 1 [5 (3 CHLORO 1H PYRAZOLO[3,4 C]PYRIDIN 5 YL) PYRIDIN 3 YLOXY] 3 PHENYLPROPAN 2 AMINE; 1 [5 (3 METHYL 1H PYRAZOLO[3,4 C]PYRIDIN 5 YL)PYRIDIN 3 YLOXY] 3 PHENYLPROPAN 2 AMINE; 1 [5 (3 TRIFLUOROMETHYL 1H INDAZOL 5 YL)PYRIDIN 3 YLOXY] 3 (1H INDOL 3 YL)PROPAN 2 AMINE; 1 [5 [3 (1 METHYL 1H PYRROL 2 YL) 1H PYRAZOLO[3,4-C]PYRIDIN 5 YL]PYRIDIN 3 YLOXY] 3 PHENYLPROPAN 2 AMINE; 1 PHENYL 3 [5 (3 PHENYL 1H PYRAZOLO[3,4-C]PYRIDIN 5 YL)PYRIDIN 3 YLOXY]PROPAN 2 AMINE; 1 PHENYL 3 [5 (3 VINYL 1H PYRAZOLO[3,4 C]PYRIDIN 5 YL)PYRIDIN 3 YLOXY]PROPAN 2 AMINE; 1-[5 [3 (FURAN 2 YL) 1H PYRAZOLO[3,4 C]PYRIDIN 5 YL]PYRIDIN 3 YLOXY] 3 PHENYLPROPAN 2 AMINE; 5 [5 (2 AMINO 3 PHENYLPROPOXY)PYRIDIN 3 YL] 3 METHYL 1H PYRAZOLO[3,4 C]PYRIDINE 6 OXIDE; 5 [5 [2 AMINO 3 (1H INDOL 3 YL)PROPOXY]PYRIDIN 3 YL] 3 CHLORO 1H INDAZOL 6 AMINE; PROTEIN KINASE B INHIBITOR; PROTEIN KINASE INHIBITOR; TERT BUTYL 1 (1H INDOL 3 YL) 3 (4 METHYL 5 NITRO 2,30 BIPYRIDIN 50 YLOXY)PROPAN 2 YLCARBAMATE; TERT BUTYL 1 (1H INDOL 3 YL) 3 (5 AMINO 4 METHYL 2,30 BIPYRIDIN 50 YLOXY)PROPAN 2 YLCARBAMATE; TERT BUTYL 5 [5 [2 (TERT BUTOXYCARBONYLAMINO) 3 PHENYLPROPOXY]PYRIDIN 3 YL] 3 CHLORO 1H PYRAZOLO [3,4 C]PYRIDINE 1 CARBOXYLATE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL INTERACTION; COMPARATIVE STUDY; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HUMANS; PANCREATIC NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; PYRAZOLES; PYRIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 33846936007     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2007.01.010     Document Type: Article

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28. Crystallization and X-ray analysis. PKA was purified, concentrated to 20 mg/mL, and complexed with PKI peptide for 1 h and then complexed with Akt inhibitors. Crystals were transferred to cryo-solutions that contained well solution plus increasing amounts of glycerol, soaking for 1 min in 5%, 15%, and 25% glycerol. Crystals were then frozen in a stream of 100 K nitrogen using an Oxford Cryo-stream cooling device. Diffraction data were recorded using a MAR-165 CCD detector system on a Rigaku RU-2000 rotating anode X-ray generator operating at 100 mA and 50 kV. Diffraction data were reduced using DENZO and the protein model (Accession No. 1YDT) with the inhibitor (H89) and the phosphorylation sites omitted from the Protein Data Bank entry 1YDT was used for initial phasing. Generation of initial electron density maps and structure refinement were achieved using CNX program package. Electron density maps were inspected on a Silicon Graphics Inc. workstation using the program QUANTA 97/2001 (Molecular Simulations Inc., San Diego, CA). Crystallographic data described in this paper have been deposited with PDB (ID for 1: 2OHO; ID for 9f: 2OJF).