ABSTRACT
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Subject(s)
Aniline Compounds/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical/methods , ErbB Receptors/metabolism , Growth Inhibitors/administration & dosage , Growth Inhibitors/chemical synthesis , Growth Inhibitors/pharmacology , Humans , Mice , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Receptor, ErbB-2/metabolismABSTRACT
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Cells, Cultured , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Humans , Indazoles , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Mice , Models, Molecular , Molecular Structure , Neoplasms/blood supply , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Receptors, Vascular Endothelial Growth Factor/chemistry , Receptors, Vascular Endothelial Growth Factor/metabolism , Sulfonamides/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
A bidirectional route to nonracemic C(2)-symmetric bistetrahydrofuran units related to acetogenin natural products was developed starting from the (S,S)-tartrate-derived dialdehyde 3.3. Bis-homologation with the (R)-alpha-OMOM crotylstannane (R)-4.1 in the presence of InCl(3) afforded the anti adduct, diol 4.3. The derived tosylate 4.4, upon treatment with TBAF in THF, underwent sequential TBS cleavage and cyclization to the (R,R,R,R,R,R)-bis-OMOM bistetrahydrofuran 4.7. The epimeric (S,R,R,R,R,S)-bis-OMOM bistetrahydrofuran 4.10 was prepared along similar lines, except that the (R)-alpha-OMOM crotylstannane (R)-4.1 was first converted to the (R)-gamma-isomer (R)-4.2 with BF(3).OEt(2). Subsequent addition of dialdehyde 3.3 led to the diol adduct 4.5, which after tosylation and treatment with TBAF, yielded the bistetrahydrofuran 4.10. By repeating the aforementioned sequences, but starting with the (S)-alpha-OMOM-crotylstannane (S)-4.1, the (S,S,R,R,S,S)- and the (R,S,R,R,S,R)-bistetrahydrofurans 5.5 and 5.8 were prepared. A variation on the foregoing sequence in which the OTBS grouping of the adduct was converted to a mesylate and the OH group was used to effect intramolecular displacement was also examined. Accordingly, adduct ent-5.3 from BF(3)-promoted addition of stannane (R)-4.2 and ent-3.3, the enantiomer of aldehyde 3.3, was acetylated. Cleavage of the TBS ether followed by mesylate formation and then concommitant acetate hydrolysis and cyclization with methanolic Triton B yielded the bis-OMOM bistetrahydrofuran 5.5. An analogous sequence was used to convert adduct 4.3 to ent-4.10. In this case, acetate saponification was effected with methanolic K(2)CO(3), and the resulting diol, 7.4, was cyclized with NaH in THF.
