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

Abstract

The evolution of picolinamide derived LRRK2 inhibitors with improved kinase off target selectivity and de-risked for AMES mutagenicity.

Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors

“…Human pharmacokinetic parameters were predicted by allometric scaling of rat clearance (rCl p ) and rat volume of distribution ( V d ). The rat fraction unbound (rf u ) was directly used as a surrogate for human fraction unbound (hf u ). , The final input required for early human does prediction is a free-drug exposure target. Despite the apparent clinical association between LRRK2 mutations and PD, insight into the underlying mechanism of how these mutations lead to disease progression is limited.…”

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

“…21 We T h i s c o n t e n t i s demonstrate herein the further utility of a kinase domain surrogate obtained by introduction of ten point mutations into checkpoint kinase 1 (CHK1). 14,22 This was used in the design and optimization of a series of fragment-derived pyrrolo[2, 3d]pyrimidine-derived LRRK2 inhibitors. Multiple X-ray crystal structures of the novel inhibitors and known literature inhibitors in complex with the surrogate rationalized compound potency and selectivity.…”

“…Ligand-bound X-ray crystal structures with off-target kinases have also been used to rationalize selectivity, as well as X-ray structures of selective LRRK2 inhibitors in complex with a humanized form of Roco4, in which two point mutations give the surrogate increased resemblance to LRRK2 . We demonstrate herein the further utility of a kinase domain surrogate obtained by introduction of ten point mutations into checkpoint kinase 1 (CHK1). , This was used in the design and optimization of a series of fragment-derived pyrrolo­[2,3- d ]­pyrimidine-derived LRRK2 inhibitors. Multiple X-ray crystal structures of the novel inhibitors and known literature inhibitors in complex with the surrogate rationalized compound potency and selectivity.…”

Discovery and Optimization of Potent, Selective, and Brain-Penetrant 1-Heteroaryl-1H-Indazole LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease

“…Pyrrolidine 14 was then subjected to a battery of in vitro and in vivo preclinical safety studies to assess tolerability and genotoxicity risks. Gratifyingly, 14 was characterized as non-genotoxic as defined by negative results in the in vivo and in vitro micronucleus (MN) assays and the 5-strain Ames assay. In a 4 day rat toxicology study, 14 was tolerated up to 50 mpk BID [ C max (unbound) = 47.4 μM (0.8 μM); AUC 0– x (unbound) = 919 μM·h (15.6 μM·h)], corresponding to a 7× exposure multiple (EM) relative to the projected human exposure and 45–70 mg BID dose; however, adverse events and mortality were observed at higher doses.…”

“…The LRRK2 field has witnessed remarkable progress toward the discovery and development of potent, kinome selective, and central nervous system (CNS) penetrant type I (ATP-competitive) kinase inhibitors (Figure B), two of which have advanced to clinical trials. − Our contributions to the field commenced with the identification of dihydrobenzothiophene and indazole series of compounds which emerged from an HTS screen against recombinant wt LRRK2. Optimization of the indazole series led to the discovery of MLi-2 (Table ), an advanced tool molecule that was made available to collaborators around the world and bolstered the industry’s collective understanding of LRRK2 biology, pharmacology, and toxicology. − More recently, we disclosed low dose, kinome selective, brain-penetrant picolinamide and aminoquinazoline LRRK2 kinase inhibitors, including “compound 24 ” ( 6 ). In what follows, we describe the invention of a 1-heteroaryl-1 H -indazole series (referred to as, “reverse indazoles”) and the discovery of spirocyclopropyl nitrile 25 , an exquisitely potent and kinome selective LRRK2 inhibitor.…”