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1.
Xenobiotica ; 53(8-9): 547-558, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37880944

ABSTRACT

Evobrutinib is a highly selective, covalent, central nervous system-penetrant Bruton's tyrosine kinase (BTK) inhibitor, currently in Phase III trials for the treatment of relapsing multiple sclerosis. One major circulating metabolite of evobrutinib has been previously identified as the racemic dihydro-diol M463-2 (MSC2430422) in a Phase I human mass balance study.Phenotyping experiments were conducted to confirm the metabolic pathway of evobrutinib to M463-2. Ratio of the enantiomers was determined by enantioselective liquid chromatography with tandem mass spectrometry analysis of plasma samples from humans and preclinical species. Drug-drug interaction (DDI) characterisation, evaluation of pharmacological activity on BTK, and off-target screening experiments followed assessing safety of the metabolite.The biotransformation of evobrutinib to M463-2 was determined to be a two-step process with a CYP-mediated oxidation acting to form an epoxide intermediate, which was further hydrolysed by soluble and mitochondrial epoxide hydrolase. Only the (S)-enantiomer was determined to be a major metabolite, the (R)-enantiomer was minor. In vitro studies demonstrated the (S)-enantiomer lacked clinically relevant pharmacological activity, off-target effects and DDIs.The biotransformation of evobrutinib to its major metabolite has been elucidated, with the major (S)-enantiomer being shown to pose no on/off target or DDI risks.


Subject(s)
Piperidines , Pyrimidines , Humans , Piperidines/pharmacology , Biotransformation , Drug Interactions , Protein Kinase Inhibitors/pharmacology
2.
Bioorg Med Chem ; 92: 117423, 2023 09 07.
Article in English | MEDLINE | ID: mdl-37531921

ABSTRACT

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.


Subject(s)
Interleukin-2 , Receptors, Antigen, T-Cell , Mice , Animals , Chlorocebus aethiops , Protein Serine-Threonine Kinases , COS Cells
3.
J Med Chem ; 64(19): 14603-14619, 2021 10 14.
Article in English | MEDLINE | ID: mdl-34596404

ABSTRACT

Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors.


Subject(s)
Neoplasms , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-akt , Ribosomal Protein S6 Kinases, 70-kDa , Animals , Humans , Cell Line, Tumor , High-Throughput Screening Assays , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/drug effects , Stereoisomerism , Structure-Activity Relationship , TOR Serine-Threonine Kinases/drug effects
4.
Bioorg Med Chem ; 40: 116163, 2021 06 15.
Article in English | MEDLINE | ID: mdl-33932711

ABSTRACT

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Imidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Agammaglobulinaemia Tyrosine Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship
5.
J Med Chem ; 62(17): 7643-7655, 2019 09 12.
Article in English | MEDLINE | ID: mdl-31368705

ABSTRACT

Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Immune System Diseases/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Administration, Oral , Agammaglobulinaemia Tyrosine Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Immune System Diseases/metabolism , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Structure-Activity Relationship
6.
ChemMedChem ; 14(2): 217-223, 2019 01 22.
Article in English | MEDLINE | ID: mdl-30521698

ABSTRACT

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.


Subject(s)
Biological Assay/methods , Piperazines/chemistry , Protein Kinase Inhibitors/analysis , Pyridines/chemistry , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Biotin/chemistry , Mice , Models, Animal , Molecular Structure , Piperazines/chemical synthesis , Protein Kinase Inhibitors/metabolism , Pyridines/chemical synthesis , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 28(21): 3419-3424, 2018 11 15.
Article in English | MEDLINE | ID: mdl-30290988

ABSTRACT

Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Adenine/analogs & derivatives , Administration, Oral , Animals , Caco-2 Cells , Humans , Mice , Molecular Structure , Piperidines , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/pharmacology , Pyridines/administration & dosage , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 28(20): 3307-3311, 2018 11 01.
Article in English | MEDLINE | ID: mdl-30243592

ABSTRACT

Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Niacinamide/pharmacology , Protein Kinase Inhibitors/pharmacology , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/chemistry , Animals , Caco-2 Cells , Catalytic Domain , Humans , Mice , Molecular Structure , Niacinamide/analogs & derivatives , Niacinamide/chemical synthesis , Niacinamide/pharmacokinetics , Permeability , Piperidines , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacology
9.
Bioorg Med Chem Lett ; 28(17): 2939-2944, 2018 09 15.
Article in English | MEDLINE | ID: mdl-30122225

ABSTRACT

Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Agammaglobulinaemia Tyrosine Kinase/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
10.
ACS Med Chem Lett ; 2(9): 650-5, 2011 Sep 08.
Article in English | MEDLINE | ID: mdl-24900360

ABSTRACT

A series of potent and selective ß1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; ß1/ß2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood pool into the myocardium (0.48-0.62% ID/g), lung (0.63-0.97% ID/g), and liver (1.03-1.14% ID/g). Dynamic µPET imaging confirmed the in vivo dissection studies.

11.
Org Lett ; 9(26): 5617-20, 2007 Dec 20.
Article in English | MEDLINE | ID: mdl-18041848

ABSTRACT

Recently developed copper-catalyzed coupling methodology has been applied to the synthesis of amino acid derived enamides. Bond formation proved to be strongly influenced by protection strategy and vinyl iodide substitution while tolerant of limited side chain functionality. Assessment of aminopeptidase activity revealed a preference for (E)-1,2-disubstituted constructs.


Subject(s)
Amides/chemical synthesis , Amino Acids/chemistry , Aminopeptidases/metabolism , Amides/chemistry
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