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61. New quinoline NK3 receptor antagonists with CNS activity

Author

Smith, Paul W., Wyman, Paul A., Lovell, Peter, Goodacre, Caroline, Serafinowska, Halina T., Vong, Antonio, Harrington, Frank, Flynn, Sean, Bradley, Daniel M., Porter, Rod, Coggon, Sara, Murkitt, Graham, Searle, Kirsten, Thomas, David R., Watson, Jeannette M., Martin, William, Wu, Zining, and Dawson, Lee A.

Subjects
*TACHYKININ antagonists, *QUINOLINE, *SULFONAMIDES, *DRUG lipophilicity, *CENTRAL nervous system, *BINDING sites
Abstract

Abstract: Lead optimisation starting from the previously reported selective quinoline NK3 receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK3 antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK3 receptor antagonists which despite having different degrees of CNS penetration produced excellent NK3 receptor occupancy in an ex vivo binding study in gerbil cortex. [Copyright &y& Elsevier]

Published
2009
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63. Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5).

Author

Callahan JF, Burgess JL, Fornwald JA, Gaster LM, Harling JD, Harrington FP, Heer J, Kwon C, Lehr R, Mathur A, Olson BA, Weinstock J, and Laping NJ

Subjects
DNA-Binding Proteins metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Fibronectins biosynthesis, Fibronectins genetics, Humans, Imidazoles chemistry, Imidazoles pharmacology, Mitogen-Activated Protein Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases, RNA, Messenger biosynthesis, Receptor, Transforming Growth Factor-beta Type I, Smad3 Protein, Structure-Activity Relationship, Trans-Activators metabolism, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases, Activin Receptors, Type I antagonists & inhibitors, Enzyme Inhibitors chemical synthesis, Imidazoles chemical synthesis, Receptors, Transforming Growth Factor beta antagonists & inhibitors
Abstract

Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.

Published
2002
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