Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology.
Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).
['Boga|Sobhana Babu|SB|', 'Alhassan|Abdul-Basit|AB|', 'Cooper|Alan B|AB|', 'Doll|Ronald|R|', 'Shih|Neng-Yang|NY|', 'Shipps|Gerald|G|', 'Deng|Yongqi|Y|', 'Zhu|Hugh|H|', 'Nan|Yang|Y|', 'Sun|Robert|R|', 'Zhu|Liang|L|', 'Desai|Jagdish|J|', 'Patel|Mehul|M|', 'Muppalla|Kiran|K|', 'Gao|Xiaolei|X|', 'Wang|James|J|', 'Yao|Xin|X|', 'Kelly|Joseph|J|', 'Gudipati|Subrahmanyam|S|', 'Paliwal|Sunil|S|', 'Tsui|Hon-Chung|HC|', 'Wang|Tong|T|', 'Sherborne|Bradley|B|', 'Xiao|Li|L|', 'Hruza|Alan|A|', 'Buevich|Alexei|A|', 'Zhang|Li-Kang|LK|', 'Hesk|David|D|', 'Samatar|Ahmed A|AA|', 'Carr|Donna|D|', 'Long|Brian|B|', 'Black|Stuart|S|', 'Dayananth|Priya|P|', 'Windsor|William|W|', 'Kirschmeier|Paul|P|', 'Bishop|Robert|R|']
D000818:Animals D000970:Antineoplastic Agents D049109:Cell Proliferation D018360:Crystallography, X-Ray D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D006801:Humans D019950:Mitogen-Activated Protein Kinase 1 D048052:Mitogen-Activated Protein Kinase 3 D008958:Models, Molecular D015394:Molecular Structure D047428:Protein Kinase Inhibitors D011759:Pyrrolidines D051381:Rats D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
ERK inhibitor Oncology ATP competitive Kinase selectivity MAP kinases