TY  - JOUR
A1  - Woodward, HL
A1  - Innocenti, P
A1  - Cheung, KMJ
A1  - Hayes, A
A1  - Roberts, J
A1  - Henley, AT
A1  - Faisal, A
A1  - Mak, GWY
A1  - Box, G
A1  - Westwood, IM
A1  - Cronin, N
A1  - Carter, M
A1  - Valenti, M
A1  - De Haven Brandon, A
A1  - O'Fee, L
A1  - Saville, H
A1  - Schmitt, J
A1  - Burke, R
A1  - Broccatelli, F
A1  - Van Montfort, RLM
A1  - Raynaud, FI
A1  - Eccles, SA
A1  - Linardopoulos, S
A1  - Blagg, J
A1  - Hoelder, S
JF  - Journal of Medicinal Chemistry
SN  - 1520-4804
UR  - http://dx.doi.org/10.1021/acs.jmedchem.8b00690
ID  - discovery10057245
N2  - Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4-d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4-d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.
N1  - This is an open access article published under an ACS AuthorChoice License (https://pubs.acs.org/page/policy/authorchoice_termsofuse.html), which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
IS  - 18
EP  - 8240
VL  - 61
AV  - public
SP  - 8226
Y1  - 2018/09/27/
TI  - Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4-d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine (BOS172722)
ER  -