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1.
J Med Chem ; 66(21): 14912-14927, 2023 11 09.
Article in English | MEDLINE | ID: mdl-37861679

ABSTRACT

Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.


Subject(s)
Parkinson Disease , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Brain/metabolism , Mutation , Ion Channels/metabolism
2.
J Med Chem ; 65(24): 16801-16817, 2022 12 22.
Article in English | MEDLINE | ID: mdl-36475697

ABSTRACT

Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp3-sp2 cross-coupling technologies. This resulted in the discovery of a unique sp3-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound, 25, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.


Subject(s)
Parkinson Disease , Rats , Humans , Animals , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Parkinson Disease/drug therapy , Indazoles/pharmacology , Indazoles/therapeutic use , Leukocytes, Mononuclear/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Brain/metabolism , Adenosine Triphosphate
3.
J Med Chem ; 65(1): 838-856, 2022 01 13.
Article in English | MEDLINE | ID: mdl-34967623

ABSTRACT

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.


Subject(s)
Antiparkinson Agents/chemical synthesis , Antiparkinson Agents/pharmacology , Brain/metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Antiparkinson Agents/pharmacokinetics , Biological Availability , Drug Design , Humans , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacokinetics , Structure-Activity Relationship
4.
RSC Med Chem ; 12(7): 1164-1173, 2021 Jul 21.
Article in English | MEDLINE | ID: mdl-34355182

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.

5.
Bioorg Med Chem Lett ; 42: 128046, 2021 06 15.
Article in English | MEDLINE | ID: mdl-33865969

ABSTRACT

PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.


Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Drug Discovery , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phthalimides/pharmacology , Class I Phosphatidylinositol 3-Kinases/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Molecular Structure , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors/chemistry , Phthalimides/chemical synthesis , Phthalimides/chemistry , Structure-Activity Relationship
6.
Nat Commun ; 10(1): 5759, 2019 12 17.
Article in English | MEDLINE | ID: mdl-31848333

ABSTRACT

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.


Subject(s)
Drug Discovery/methods , Enzyme Inhibitors/pharmacology , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Molecular Probes/pharmacology , Crystallography, X-Ray , DNA Methylation/drug effects , Enzyme Inhibitors/chemistry , HEK293 Cells , Histone-Lysine N-Methyltransferase/metabolism , Histone-Lysine N-Methyltransferase/ultrastructure , Histones/metabolism , Humans , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Molecular Probes/chemistry , Protein Domains , S-Adenosylmethionine/metabolism
7.
Bioorg Med Chem Lett ; 22(9): 3203-7, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22483609

ABSTRACT

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.


Subject(s)
Amides/chemical synthesis , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Alzheimer Disease/drug therapy , Amides/pharmacology , Amyloid beta-Peptides/biosynthesis , Animals , Brain/drug effects , Brain/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Mice , Peptide Fragments/biosynthesis
8.
Bioorg Med Chem Lett ; 19(4): 1168-72, 2009 Feb 15.
Article in English | MEDLINE | ID: mdl-19138845

ABSTRACT

The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.


Subject(s)
Histone Deacetylase Inhibitors , Animals , Combinatorial Chemistry Techniques , Dogs , Drug Design , Histone Deacetylase 1 , Histone Deacetylase 2 , Humans , Molecular Structure , Rats , Repressor Proteins/antagonists & inhibitors , Structure-Activity Relationship , Xenograft Model Antitumor Assays
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