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 RelationshipABSTRACT
In the title compound, C(17)H(16)O(2), the dihedral angle between the aromatic rings is 5.12â (13)° and an intra-molecular O-Hâ¯O hydrogen bond generates an S(6) ring.
ABSTRACT
The mol-ecule of the title compound, C(17)H(16)O(3), exists in the E conformation with respect to the central C=C bond, is almost planar(r.m.s. deviation = 0.003â Å) and has an intra-molecular O-Hâ¯O hydrogen bond, which generates an S(6) ring. In the crystal, mol-ecules are linked by C-Hâ¯O inter-actions.
ABSTRACT
In the structure of the title compound, C(15)H(14)O(2)S, the benzene ring is nearly coplanar with the thio-phene ring. The hydroxy group substituted at C2 position is in an antiperi-planar conformation with respect to the phenyl ring. The crystal structure exhibits weak intramolecular O-Hâ¯O hydrogen bonding.
