Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'. Issue 21 (1st November 2020)

• Record Type: Journal Article
• Authors: Hirst, David J.; Brandt, Martin; Bruton, Gordon; Christodoulou, Erica; Cutler, Leanne; Deeks, Nigel; Goodacre, Jonathan D.; Jack, Torquil; Lindon, Matthew; Miah, Afjal; Page, Kevin; Parr, Nigel; Shukla, Lena; Sims, Martin; Thomas, Pamela; Thorpe, James; Holmes, Duncan S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 21(2020)
• Publication Date: 2020-11-01
• Subjects: Methionine aminopeptidase-2 -- MetAP-2 -- Molecular budget -- Structure-based drug design -- Indole carboxamide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127533
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physicochemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model.