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

DOI: 10.1021/acs.jmedchem.1c00720

Authors: Douglas S. Williamson (Vernalis (R&D) Ltd) , Garrick P. Smith (H. Lundbeck A/S) , Gitte K. Mikkelsen (H. Lundbeck A/S) , Thomas Jensen (H. Lundbeck A/S) , Pamela Acheson-Dossang (Vernalis (R&D) Ltd) , Lassina Badolo (H. Lundbeck A/S) , Simon T. Bedford (Vernalis (R&D) Ltd) , Victoria Chell (Vernalis (R&D) Ltd) , I-Jen Chen (Vernalis (R&D) Ltd) , Pawel Dokurno (Vernalis (R&D) Ltd) , Morten Hentzer (H. Lundbeck A/S) , Stephanie Newland (Vernalis (R&D) Ltd) , Stuart C. Ray (Vernalis (R&D) Ltd) , Terry Shaw (Vernalis (R&D) Ltd) , Allan E. Surgenor (Vernalis (R&D) Ltd) , Lindsey Terry (Vernalis (R&D) Ltd) , Yikang Wang (Vernalis (R&D) Ltd) , Kenneth V. Christensen (H. Lundbeck A/S)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 27063 , 2103 , 5791 , 6001

Abstract: 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 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-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 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 44 and 45 demonstrated high potency and exquisite selectivity for LRRK2 and utility as chemical probes for the study of LRRK2 inhibition.

Journal Keywords: X-rays; Peptides and proteins; Ligands; Chemical structure; Rodent models

Diamond Keywords: Parkinson’s Disease

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: Proxima1 at Soleil; id29 at ESRF

Added On: 07/07/2021 08:47

Documents:
acs.jmedchem.1c00720.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)