4HLE

Compound 21 (1-alkyl-substituted 1,2,4-triazoles)

Summary for 4HLE

• Entry DOI: 10.2210/pdb4hle/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-4,5-dihydrothieno[3,2-d][1]benzoxepine-8-carboxamide (2 entities in total)
• Functional Keywords: lipid kinase, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111081.53

Authors

Murray, J.M.,Rouge, L.,Wu, P. (deposition date: 2012-10-16, release date: 2013-01-09, Last modification date: 2024-02-28)

Primary citation

Staben, S.T.,Blaquiere, N.,Tsui, V.,Kolesnikov, A.,Do, S.,Bradley, E.K.,Dotson, J.,Goldsmith, R.,Heffron, T.P.,Lesnick, J.,Lewis, C.,Murray, J.,Nonomiya, J.,Olivero, A.G.,Pang, J.,Rouge, L.,Salphati, L.,Wei, B.,Wiesmann, C.,Wu, P.
Cis-Amide isosteric replacement in thienobenzoxepin inhibitors of PI3-kinase.
Bioorg.Med.Chem.Lett., 23:897-901, 2013

PubMed Abstract: Substructural class effects surrounding replacement of a 'cis' N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability.

PubMed: 23265894
DOI: 10.1016/j.bmcl.2012.10.121

Experimental method

X-RAY DIFFRACTION (2.78 Å)