1.
Bioorg Med Chem Lett
; 22(13): 4377-85, 2012 Jul 01.
Article
in English
| MEDLINE
| ID: mdl-22632936
ABSTRACT
Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.
Subject(s)
Adenine/analogs & derivatives , Morpholines/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Purines/chemistry , Adenine/chemistry , Adenine/pharmacokinetics , Adenine/toxicity , Administration, Oral , Animals , Apoptosis/drug effects , Binding Sites , Crystallography, X-Ray , G2 Phase Cell Cycle Checkpoints/drug effects , HCT116 Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , Mice , Molecular Conformation , Morpholines/pharmacokinetics , Morpholines/toxicity , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/toxicity , Protein Serine-Threonine Kinases/metabolism , Structure-Activity Relationship
2.
Bioorg Med Chem Lett
; 18(24): 6377-80, 2008 Dec 15.
Article
in English
| MEDLINE
| ID: mdl-18996008
ABSTRACT
Efforts towards developing orally bioavailable HIV-1 maturation inhibitors starting from betulinic acid 1 are described. SAR resulted in improved potency, physicochemical properties, and enhanced oral absorption in rats.
