942070-38-4Relevant articles and documents
Synthesis of Novel Pyrazine-Substituted 1 H -Pyrrole-2-carboxamides and Related Tethered Heterocycles
Borrows, Rachel,Fairley, Gary,Feron, Lyman J. L.,Grant, Emma,Greenwood, Ryan D. R.,Howells, Rachel L.,Hughes, Samantha,Lamont, Scott G.,Lenz, Eva,McGuire, Thomas M.,Simpson, Iain
, (2022/02/10)
As part of a drug discovery program, 4-pyrazin-2-yl-1H-pyrrole-2-carboxamides were accessed along with a number of bicyclic analogues. Routes to these compounds were largely absent from the scientific literature. The synthesis of a 4-(pyrazin-2-yl)-1H-pyrrole-2-carboxamide and several fused bicyclic analogues all using standard procedures (SNAr, borylation, C C cross couplings, hydrolysis, amide bond formation, cyclisation, halogenation, and alkylation) from readily available starting materials is reported. The synthetic sequences range from 4-2 steps per final compound, with yields of isolated intermediates ranging from 20 to ?100%.
Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)
Ward, Richard A.,Anderton, Mark J.,Bethel, Paul,Breed, Jason,Cook, Calum,Davies, Emma J.,Dobson, Andrew,Dong, Zhiqiang,Fairley, Gary,Farrington, Paul,Feron, Lyman,Flemington, Vikki,Gibbons, Francis D.,Graham, Mark A.,Greenwood, Ryan,Hanson, Lyndsey,Hopcroft, Philip,Howells, Rachel,Hudson, Julian,James, Michael,Jones, Clifford D.,Jones, Christopher R.,Li, Yongchao,Lamont, Scott,Lewis, Richard,Lindsay, Nicola,McCabe, James,McGuire, Thomas,Rawlins, Philip,Roberts, Karen,Sandin, Linda,Simpson, Iain,Swallow, Steve,Tang, Jia,Tomkinson, Gary,Tonge, Michael,Wang, Zhenhua,Zhai, Baochang
supporting information, p. 11004 - 11018 (2019/12/02)
The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.
Synthetic strategies for the synthesis and transformation of substituted pyrrolinones as advanced intermediates for rhazinilam analogues
Kholod, Inga,Vallat, Olivier,Buciumas, Ana-Maria,Neels, Antonia,Neier, Reinhard
, p. 7865 - 7877 (2015/03/04)
The biaryl core structure of rhazinilam with its fixed dihedral angle is a pivotal element for its unique in vitro cytotoxic activity. Most of the related natural products are oxidized versions of rhazinilam. Replacing the sensitive pyrrole ring by a pyrrolinone ring is the basis of our initial strategy towards rhazinilam analogues. With this goal, variants of the sequence crossed Mukaiyama aldol reaction followed by the Staudinger reaction were studied. Reacting a suitably substituted acetophenone with O-methyl O-trimethylsilyl ketene acetal gave pyrrolinones 8a and 8b in good to excellent yields. These intermediates could be transformed in four high-yielding steps into the pyrrolic precursors 7a-c containing all the atoms necessary for the construction of rings A, B, and C of rhazinilam. Our studies illustrate a lack of stability of these intermediates. Alternative synthetic approaches towards this central biaryl core structure are described.
