Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability

Young, Wendy B.; Barbosa, James A.; Blomgren, Peter; Bremer, Meire; Crawford, James J.; Dambach, Donna M.; Gallion, Steve; Johnson, Adam R.; Kropf, Jeffrey E.; Lee, Seung H.; Liu, Lichuan; Lubach, Joseph W.; Macaluso, Jen; Maciejewski, Pat; Mitchell, Scott A.; Ortwine, Daniel F.; Paolo, Julie Di; Reif, Karin; Scheerens, Heleen; Schmitt, Aaron C.; Wong, Harvey; Xiong, Jin-Ming; Xu, Jianjun; Yu, Christine; Zhao, Zheng; Currie, Kevin S.

doi:10.1016/j.bmcl.2015.11.076

Cited by 37 publications

(26 citation statements)

References 13 publications

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“…9−11,16 Their high potency and selectivity stems from the ability of compounds such as 1 to create an induced binding fit in the protein via a rearrangement of the activation loop. 3 Other kinases, including members of the tyrosine kinase family, cannot rearrange in the exact same way due to differences in the amino acid sequence within this loop.…”

mentioning

confidence: 99%

Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties

Wang¹,

Barbosa

Blomgren

et al. 2017

ACS Med. Chem. Lett.

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In our continued effort to discover and develop best-in-class Bruton’s tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.

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mentioning

confidence: 99%

Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties

Wang¹,

Barbosa

Blomgren

et al. 2017

ACS Med. Chem. Lett.

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“…SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead a analog, possessing improved potency, metabolic stability and preclinical properties (Young at al., 2016). Pyridazinone derivative, compound 3711, as a nonnucleosidic hepatitis B virus (HBV) inhibitor in a cell model system, decreased extracellular HBV DNA levels by 50% (50% inhibitory concentration [IC50]) at 1.5 μM and intracellular DNA levels at 1.9 μM, which exhibited antiviral activity.…”

Section: Biological Activitiesmentioning

confidence: 99%

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

Int¹

2019

Preprint

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A series of heterocyclic compounds incorporating pyridazine moiety were for diverse biological activities. Pyridazines and pyridazinones derivatives showed wide spectrum of biological activities such as vasodialator, cardiotonic, anticonvulsant, antihypertensive, antimicrobial, anti-inflammatory, analgesic, anti-feedant, herbicidal, and various other biological, agrochemical and industrial chemical activities. The results illustrated that the synthesized pyridazine/pyridazine compounds have diverse and significant biological activities. Mechanistic insights into the biological properties of pyridazinone derivatives and various synthetic techniques used for their synthesis are also described.

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“…1). Although this compound failed in the clinic, the study findings allowed the project team to concentrate their efforts on removing this liability in subsequent compounds and advance candidates with optimized pharmacokinetic properties (Young et al, 2016).…”

Section: Aldehyde Oxidasementioning

confidence: 99%

“…At that time, from a preclinical, drug discovery point of view, it was sufficient to measure the rates of metabolism in hepatocytes or liver cytosol and ultimately remove this metabolic liability without knowing the specific enzyme(s) involved (Young et al, 2016). Selective chemical inhibitors and recombinant enzymes are commonly used for the purpose of reaction phenotyping for a handful of enzymes, mainly P450, FMO, UGT, and AO.…”

Section: Aldehyde Oxidasementioning

confidence: 99%

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

Pw¹,

Zhang²,

Js³

et al. 2016

Drug Metabolism and Disposition

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The significant roles that cytochrome P450 (P450) and UDPglucuronosyl transferase (UGT) enzymes play in drug discovery cannot be ignored, and these enzyme systems are commonly examined during drug optimization using liver microsomes or hepatocytes. At the same time, other drug-metabolizing enzymes have a role in the metabolism of drugs and can lead to challenges in drug optimization that could be mitigated if the contributions of these enzymes were better understood. We present examples (mostly from Genentech) of five different non-P450 and non-UGT enzymes that contribute to the metabolic clearance or bioactivation of drugs and drug candidates. Aldehyde oxidase mediates a unique amide hydrolysis of ,7-tetrahydro-1-benzothiophene-2-carboxamide), leading to high clearance of the drug. Likewise, the rodent-specific ribose conjugation by ADP-ribosyltransferase leads to high clearance of an interleukin-2-inducible T-cell kinase inhibitor. Metabolic reactions by flavin-containing monooxygenases (FMO) are easily mistaken for P450-mediated metabolism such as oxidative defluorination of 4-fluoro-N-methylaniline by FMO. Gamma-glutamyl transpeptidase is involved in the initial hydrolysis of glutathione metabolites, leading to formation of proximate toxins and nephrotoxicity, as is observed with cisplatin in the clinic, or renal toxicity, as is observed with efavirenz in rodents. Finally, cathepsin B is a lysosomal enzyme that is highly expressed in human tumors and has been targeted to release potent cytotoxins, as in the case of brentuximab vedotin. These examples of non-P450-and non-UGT-mediated metabolism show that a more complete understanding of drug metabolizing enzymes allows for better insight into the fate of drugs and improved design strategies of molecules in drug discovery.

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Discovery of highly potent and selective Bruton’s tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability

Cited by 37 publications

References 13 publications

Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties

Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

Going Beyond Common Drug Metabolizing Enzymes: Case Studies of Biotransformation Involving Aldehyde Oxidase, -Glutamyl Transpeptidase, Cathepsin B, Flavin-Containing Monooxygenase, and ADP-Ribosyltransferase

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