Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures.

1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of Na1.7 inhibition.

Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit Na1.7 and demonstrate high levels of selectivity over other Na isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity.

The discovery of benzoxazine sulfonamide inhibitors of Na1.7: Tools that bridge efficacy and target engagement.

The voltage-gated sodium channel Na1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na1.

Sulfonamides as Selective Na1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity.

Because of its strong genetic validation, Na1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as Na1.

Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity.

There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists.

Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.

Direct, Regioselective N-Alkylation of 1,3-Azoles.

Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom.

Development of novel azabenzofuran TRPA1 antagonists as in vivo tools.

The transient receptor potential ankyrin 1 (TRPA1) channel is activated by noxious stimuli including chemical irritants and endogenous inflammatory mediators. Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A novel azabenzofuran series was developed that demonstrated in vitro inhibition of allyl isothiocyanate (AITC)-induced (45)Ca(2+) uptake with nanomolar potencies against both human and rat TRPA1.

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads.

Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors.

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.

Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series.

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly.

Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.

mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα.

Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain.

Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain.

Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles.

Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo.

AMG 458 {1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide} is a potent, selective inhibitor of c-Met, a receptor tyrosine kinase that is often deregulated in cancer. AMG 458 was observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. When [(14)C]AMG 458 was incubated with liver microsomes in the presence of glutathione and N-acetyl cysteine, thioether adducts were detected by radiochromatography and LC/MS/MS analysis.

Synthesis and activity of substituted carbamates as potentiators of the alpha4beta2 nicotinic acetylcholine receptor.

The synthesis and structure-activity relationship of a series of carbamate potentiators of alpha4beta2 nAChR is reported herein. These compounds were highly selective for alpha4beta2 over other nAChR subtypes. In addition, compounds increased the response of alpha4beta2 nAChRs to acetylcholine, as measured with patch-clamp electrophysiology.

Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators.

The discovery of a series of small molecule alpha4beta2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha3beta2 and alpha3beta4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha4beta2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine.

Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types.

Catalytic asymmetric addition of diorganozinc reagents to N-phosphinoylalkylimines.

The synthesis of alpha-chiral amines bearing two alkyl groups has been hampered by the accessibility and stability of the alkylimine precursor. Herein, we report an efficient strategy to generate the alkyl-substituted imine in situ that is compatible with the Me-DuPHOS monoxide.Cu(I) catalyzed addition of diorganozinc reagents.

Asymmetric, catalytic synthesis of alpha-chiral amines using a novel bis(phosphine) monoxide chiral ligand.

We have shown that Me-DuPHOS monoxide (BozPHOS) is a very effective ligand in the copper-catalyzed addition of dialkylzinc to N-phosphinoylimines providing access to alpha-chiral amines. The new ligand is particularly effective for the addition of the lesser reactive dimethylzinc. The major advantages of this process are high yields, broad substrate scope, and high enantioselectivities with low catalyst loading (3 mol %).

Orthoacylimines: a new class of chiral auxiliaries for nucleophilic addition of organolithium reagents to imines.

A new class of orthoacylimine-derived chiral auxiliaries has been synthesized and tested in the nucleophilic addition of organolithium reagents to imines. The precursors can be prepared by an aza-Wittig reaction between the corresponding orthoacyl azide and a variety of aldehydes in the presence of trialkylphosphines. The nucleophilic addition of organolithium reagents led to the addition products in good yields and with good to excellent diastereoselectivities (from 85:15 to 99:1).