Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology

  • Bioorg Med Chem Lett. 2018 Jun 15;28(11):2029-2034. doi: 10.1016/j.bmcl.2018.04.063.
Sobhana Babu Boga  1 ,  Abdul-Basit Alhassan  2 ,  Alan B Cooper  2 ,  Ronald Doll  2 ,  Neng-Yang Shih  2 ,  Gerald Shipps  3 ,  Yongqi Deng  3 ,  Hugh Zhu  2 ,  Yang Nan  3 ,  Robert Sun  2 ,  Liang Zhu  3 ,  Jagdish Desai  2 ,  Mehul Patel  3 ,  Kiran Muppalla  3 ,  Xiaolei Gao  2 ,  James Wang  2 ,  Xin Yao  2 ,  Joseph Kelly  2 ,  Subrahmanyam Gudipati  2 ,  Sunil Paliwal  2 ,  Hon-Chung Tsui  2 ,  Tong Wang  3 ,  Bradley Sherborne  2 ,  Li Xiao  2 ,  Alan Hruza  2 ,  Alexei Buevich  2 ,  Li-Kang Zhang  2 ,  David Hesk  2 ,  Ahmed A Samatar  2 ,  Donna Carr  2 ,  Brian Long  2 ,  Stuart Black  2 ,  Priya Dayananth  2 ,  William Windsor  2 ,  Paul Kirschmeier  2 ,  Robert Bishop  2
Affiliations
  • 1. Discovery Chemistry, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States. Electronic address: [email protected].
  • 2. Discovery Chemistry, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
  • 3. Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
PMID: 29748051 DOI: 10.1016/j.bmcl.2018.04.063
Abstract

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).

Keywords
ATP competitive; ERK inhibitor; Kinase selectivity; MAP kinases; Oncology.
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