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. published the artcile< 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>, Reference of 69205-79-4, the main research area is pyrrolopyrimidine preparation leucine rich repeat kinase Parkinson crystal structure.
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 I (LRRK2 G2019S cKi 0.7 nM, LE 0.66) was identified, with increased potency consistent with an X-ray structure of 18/CHK1 10-pt. mutant showing the 2-Me substituent proximal to Ala147 (Ala2016 in LRRK2). Further structure-guided elaboration of I gave the 2-[(1,3-dimethyl-1H-pyrazol-4-yl)amino] deriv II. Optimization of II afforded diastereomeric oxolan-3-yl derivatives III and IV, which demonstrated a favorable in vitro PK profile, although they displayed species disconnects in the in vivo PK profile, and a propensity for P-gp- and/or BCRP-mediated efflux in a mouse model. Compounds III and IV demonstrated high potency and exquisite selectivity for LRRK2 and utility as chem. probes for the study of LRRK2 inhibition.
Journal of Medicinal Chemistry published new progress about Crystal structure. 69205-79-4 belongs to class nitriles-buliding-blocks, and the molecular formula is C7H5N5O, Reference of 69205-79-4.
Referemce:
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts