Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'.
Indole carboxamide
MetAP-2
Methionine aminopeptidase-2
Molecular budget
Structure-based drug design
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 11 2020
01 11 2020
Historique:
received:
28
05
2020
revised:
22
08
2020
accepted:
29
08
2020
pubmed:
13
9
2020
medline:
23
6
2021
entrez:
12
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32919012
pii: S0960-894X(20)30644-2
doi: 10.1016/j.bmcl.2020.127533
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Indoles
0
indole
8724FJW4M5
METAP2 protein, human
EC 3.4.11.18
Methionyl Aminopeptidases
EC 3.4.11.18
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
127533Informations de copyright
Copyright © 2020. Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.