eprintid: 10057245 rev_number: 18 eprint_status: archive userid: 608 dir: disk0/10/05/72/45 datestamp: 2018-10-01 16:56:31 lastmod: 2021-09-17 22:29:43 status_changed: 2018-10-01 16:56:31 type: article metadata_visibility: show creators_name: Woodward, HL creators_name: Innocenti, P creators_name: Cheung, KMJ creators_name: Hayes, A creators_name: Roberts, J creators_name: Henley, AT creators_name: Faisal, A creators_name: Mak, GWY creators_name: Box, G creators_name: Westwood, IM creators_name: Cronin, N creators_name: Carter, M creators_name: Valenti, M creators_name: De Haven Brandon, A creators_name: O'Fee, L creators_name: Saville, H creators_name: Schmitt, J creators_name: Burke, R creators_name: Broccatelli, F creators_name: Van Montfort, RLM creators_name: Raynaud, FI creators_name: Eccles, SA creators_name: Linardopoulos, S creators_name: Blagg, J creators_name: Hoelder, S title: 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) ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F85 note: 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. abstract: 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. date: 2018-09-27 date_type: published official_url: http://dx.doi.org/10.1021/acs.jmedchem.8b00690 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1587767 doi: 10.1021/acs.jmedchem.8b00690 lyricists_name: Woodward, Hannah lyricists_id: HKWOO61 actors_name: Dewerpe, Marie actors_id: MDDEW97 actors_role: owner full_text_status: public publication: Journal of Medicinal Chemistry volume: 61 number: 18 pagerange: 8226-8240 issn: 1520-4804 citation: Woodward, HL; Innocenti, P; Cheung, KMJ; Hayes, A; Roberts, J; Henley, AT; Faisal, A; ... Hoelder, S; + view all <#> Woodward, HL; Innocenti, P; Cheung, KMJ; Hayes, A; Roberts, J; Henley, AT; Faisal, A; Mak, GWY; Box, G; Westwood, IM; Cronin, N; Carter, M; Valenti, M; De Haven Brandon, A; O'Fee, L; Saville, H; Schmitt, J; Burke, R; Broccatelli, F; Van Montfort, RLM; Raynaud, FI; Eccles, SA; Linardopoulos, S; Blagg, J; Hoelder, S; - view fewer <#> (2018) 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). Journal of Medicinal Chemistry , 61 (18) pp. 8226-8240. 10.1021/acs.jmedchem.8b00690 <https://doi.org/10.1021/acs.jmedchem.8b00690>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10057245/1/acs.jmedchem.8b00690.pdf