Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors.
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.
Department of Medicinal Chemistry, Myrexis Inc., 305 Chipeta Way, Salt Lake City, UT 84108, USA. dvijayku@hotmail.com
D
D
Vijay Kumar
Christophe
C
Hoarau
Matthew
M
Bursavich
Paul
P
Slattum
David
D
Gerrish
Kraig
K
Yager
Michael
M
Saunders
Mark
M
Shenderovich
Bruce L
BL
Roth
Rena
R
McKinnon
Ashley
A
Chan
Daniel M
DM
Cimbora
Chad
C
Bradford
Leslie
L
Reeves
Scott
S
Patton
Damon I
DI
Papac
Brandi L
BL
Williams
Robert O
RO
Carlson
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D018360:Crystallography, X-Ray; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D008968:Molecular Conformation; D009025:Morpholines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry*; D013329:Structure-Activity Relationship
C571997:MPI-0479605; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011687:Purines; C441620:Ttk protein, mouse; D017346:Protein Serine-Threonine Kinases; D000225:Adenine; C030985:purine