27382-01-0Relevant articles and documents
Design and Synthesis of Pyrrolo[2,3-d]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate
Williamson, Douglas S.,Smith, Garrick P.,Mikkelsen, Gitte K.,Jensen, Thomas,Acheson-Dossang, Pamela,Badolo, Lassina,Bedford, Simon T.,Chell, Victoria,Chen, I-Jen,Dokurno, Pawel,Hentzer, Morten,Newland, Samantha,Ray, Stuart C.,Shaw, Terry,Surgenor, Allan E.,Terry, Lindsey,Wang, Yikang,Christensen, Kenneth V.
supporting information, p. 10312 - 10332 (2021/07/26)
Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson’s disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18 /CHK1 10-pt. mutant showing the 2-methyl substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of 18 gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] derivative 32 . Optimization of 32 afforded diastereomeric oxolan-3-yl derivatives 44 and 45 , which demonstrated a favorablein vitroPK profile, although they displayed species disconnects in thein vivoPK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.