The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors

Smith, Garrick; Badolo, Lassina; Chell, Victoria; Chen, I‐Jen; Christensen, Kenneth Vielsted; David, Laurent; Daechsel, Justus Alfred; Hentzer, Morten; Herzig, Martin C.; Mikkelsen, Gitte Kobberøe; Watson, Steve P.; Williamson, D.S.

doi:10.1016/j.bmcl.2017.07.072

Cited by 15 publications

(14 citation statements)

References 12 publications

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“…These included mixed-lineage kinase (MLK1), the crystal structure 3DTC 63 of which has formed the basis of LRRK2 homology models previously reported. 39,55,54 CHK1 was selected as a start point, however, guided by previous in-house experience of the expression, purification and crystallization of CHK1 constructs to enable ligand-bound X-ray crystal structures, and their utility in the design of novel inhibitors of this kinase for the treatment of cancer. 64,65 An initial selection of ten residues in CHK1 to be mutated ( Figure 2) was based on their <4 Å proximity to 1 in the published ligand bound X-ray structure with CHK1, 1NVR ( Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…LRRK2 kinase domain inhibitors previously reported (Figure ) range from broad spectrum kinase inhibitors such as staurosporine 1 , to more selective inhibitors such as aminopyrimidobenzodiazepinone 2 (LRRK2-IN-1), which have poor CNS penetration. Further efforts have led to the discovery of CNS penetrant, selective inhibitors such as arylbenzamide 3a (GSK2578215A), aminopyrimidine 4a (GNE-7915), pyrrolopyrimidines 5 (PF-06447475) and 6 (JH-II-127), indazole 7 (MLi-2), , and aminopyridine 8 . There has not yet, however, been a report on the progression of a compound into the clinic, which would require sufficient target engagement and an acceptable pharmacokinetic and safety profile. , …”

Section: Introductionmentioning

confidence: 99%

“…Mutated residues are highlighted in magenta. Polar intermolecular contacts <3.3 Å are shown as dashed lines.The LRRK2 G2019S activity of 41 LRRK2 inhibitors previously described in the literature, including 2-aminopyridines,39 and also pyrrolopyridines disclosed herein was determined, and compared with binding affinity for CHK1 10-pt. mut.…”

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confidence: 99%

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Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1)

et al. 2017

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Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC data for 22 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-point mutant structure). Compound 22 was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC values for 22 in mouse brain and kidney being 1.3 and 5 nM, respectively.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1)

et al. 2017

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“…5−9 LRRK2 kinase domain inhibitors previously reported (Chart 1) range from the first selective inhibitors such as aminopyrimido-benzodiazepinone 1 (LRRK2-IN-1), 10 which have poor CNS penetration, to CNS penetrant, selective inhibitors such as aminopyrimidines 2 and 3 (GNE-7915 11 and GNE-0877 12 ), indazole 4 (MLi-2 13 ), pyrrolo[2,3-b]pyridine 5, 14 and 2-aminopyridine 6. 15 There have been reports on the progression of two CNS-penetrant small molecules that inhibit LRRK2 in clinical studies; DNL201 and DNL151 (structures not disclosed). 16 The structural complexity of LRRK2, 17 a large multi-domain protein, is such that reports of stable, soluble, crystallizable kinase domain constructs to facilitate inhibitor design are limited.…”

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2021

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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 cK i 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.

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“…In the absence of high-resolution structures, the research has turned to molecular modeling and structural surrogate approach. Several models for the LRRK2 kinase domain have been developed, but they are mostly used in house and are not available for common use [85,[94][95][96][97][98][99]. Some of them have been used for virtual screening for new inhibitors [96] and even de novo inhibitor design [94].…”

Section: Rational Design Of Improved Atp-competitive Kinase Inhibitorsmentioning

confidence: 99%

LRRK2 Targeting Strategies as Potential Treatment of Parkinson’s Disease

Wojewska

Kortholt

2021

Biomolecules

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Parkinson’s Disease (PD) affects millions of people worldwide with no cure to halt the progress of the disease. Leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of PD and, as such, LRRK2 inhibitors are promising therapeutic agents. In the last decade, great progress in the LRRK2 field has been made. This review provides a comprehensive overview of the current state of the art, presenting recent developments and challenges in developing LRRK2 inhibitors, and discussing extensively the potential targeting strategies from the protein perspective. As currently there are three LRRK2-targeting agents in clinical trials, more developments are predicted in the upcoming years.

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The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors

Cited by 15 publications

References 12 publications

Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1)

Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1)

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

LRRK2 Targeting Strategies as Potential Treatment of Parkinson’s Disease

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