Download MendeleyStructure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'.
Hirst, D.J., Brandt, M., Bruton, G., Christodoulou, E., Cutler, L., Deeks, N., Goodacre, J.D., Jack, T., Lindon, M., Miah, A., Page, K., Parr, N., Shukla, L., Sims, M., Thomas, P., Thorpe, J., Holmes, D.S.(2020) Bioorg Med Chem Lett 30: 127533-127533
- PubMed: 32919012
- DOI: https://doi.org/10.1016/j.bmcl.2020.127533
- Primary Citation of Related Structures:
7A12, 7A13, 7A14, 7A15, 7A16 - PubMed 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.
Organizational Affiliation:
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: [email protected].
