Issue 7, 2021

Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors

Abstract

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound 1 by modifying the heteroaryl C–H hinge and linker regions. This resulted in compound 12 which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite 14 was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine 15 and 4,6-diaminopyrimidine 16 as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs 17 and 18 led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole 23 with excellent LRRK2 potency and expanded selectivity versus off-target CLK2.

Graphical abstract: Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors

  • This article is part of the themed collection: NeuroMedChem

Supplementary files

Article information

Article type
Research Article
Submitted
18 Mar 2021
Accepted
06 May 2021
First published
04 Jun 2021

RSC Med. Chem., 2021,12, 1164-1173

Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors

A. Gulati, C. S. Yeung, B. Lapointe, S. D. Kattar, H. Gunaydin, J. D. Scott, K. K. Childers, J. L. Methot, V. Simov, R. Kurukulasuriya, B. Pio, G. J. Morriello, P. Liu, H. Tang, S. Neelamkavil, H. B. Wood, V. L. Rada, M. J. Ardolino, X. C. Yan, R. Palte, K. Otte, R. Faltus, J. Woodhouse, L. G. Hegde, P. Ciaccio, E. C. Minnihan, E. F. DiMauro, M. J. Fell, P. H. Fuller and J. M. Ellis, RSC Med. Chem., 2021, 12, 1164 DOI: 10.1039/D1MD00097G

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements