Electric Literature of C6H3Cl2N3In 2021 ,《Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor》 appeared in Journal of Medicinal Chemistry. The author of the article were Czako, Barbara; Sun, Yuting; McAfoos, Timothy; Cross, Jason B.; Leonard, Paul G.; Burke, Jason P.; Carroll, Christopher L.; Feng, Ningping; Harris, Angela L.; Jiang, Yongying; Kang, Zhijun; Kovacs, Jeffrey J.; Mandal, Pijus; Meyers, Brooke A.; Mseeh, Faika; Parker, Connor A.; Yu, Simon S.; Williams, Christopher C.; Wu, Qi; Di Francesco, Maria Emilia; Draetta, Giulio; Heffernan, Timothy; Marszalek, Joseph. R.; Kohl, Nancy E.; Jones, Philip. The article conveys some information:
Src homol. 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-mol. therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-á-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo. The results came from multiple reactions, including the reaction of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Electric Literature of C6H3Cl2N3)
2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. Pyrimidine nucleotide derivatives have a wide range of biological applications. For example, pyrimidine derivatives are useful in DNA repair studies involving cancer and epigenetics. Electric Literature of C6H3Cl2N3
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia