Pharmacokinetics and Safety of the Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Chinese Subjects.

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, blocks cytokine signaling involved in psoriasis pathogenesis. This ethnic-bridging study evaluated deucravacitinib pharmacokinetics, tolerability, and safety in healthy Chinese subjects.

Methods: This phase I, double-blind, single-/multiple-dose study randomized healthy Chinese subjects 4:1 to a single dose of deucravacitinib 6 mg or placebo (group 1) or deucravacitinib 12 mg or placebo (group 2) on day 1; groups 1 and 2 received deucravacitinib 6 mg and 12 mg once daily, respectively, or placebo on days 5-19.

Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans.

Deucravacitinib is an oral, selective, allosteric inhibitor of tyrosine kinase 2, an intracellular signaling kinase involved in the pathogenesis of immune-mediated inflammatory diseases. The absolute and relative bioavailability (BA) were evaluated in phase 1, open-label studies in healthy adults to assess (1) the absolute BA of the deucravacitinib tablet formulation following single oral administration of a 12-mg tablet and an intravenous microdose infusion of 0.1-mg carbon-13 and nitrogen-15-labeled deucravacitinib ([ C , N ] deucravacitinib) solution in 8 subjects, and (2) the relative oral BA of deucravacitinib tablet and capsule formulations at the 3- and 12-mg dose levels in 20 subjects.

Lack of Electrocardiographic Effects of Deucravacitinib in Healthy Subjects.

Deucravacitinib is a novel, oral, selective inhibitor of the intracellular signaling kinase tyrosine kinase 2. This phase 1, randomized, partially double-blind, 4-period crossover study in healthy adults was conducted to determine whether deucravacitinib 12 mg (therapeutic dose) or 36 mg (supratherapeutic dose) had a clinically relevant effect on the corrected QT interval and other electrocardiographic (ECG) parameters. Subjects received 1 of 4 sequences of placebo, deucravacitinib 12 mg, deucravacitinib 36 mg, and moxifloxacin 400 mg (positive control) in a randomized crossover fashion.

Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors.

Introduction: Deucravacitinib, a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling, acts via an allosteric mechanism by binding to the enzyme's regulatory domain instead of the catalytic domain. This unique binding provides high functional selectivity for TYK2 versus the closely related Janus kinases (JAKs) 1/2/3. Deucravacitinib was efficacious in phase 2 and 3 psoriasis trials, without clinical or laboratory parameters indicative of JAK 1/2/3 inhibition being observed.

Pharmacokinetics of 40 kDa Polyethylene glycol (PEG) in mice, rats, cynomolgus monkeys and predicted pharmacokinetics in humans.

Conjugation with polyethylene glycol (PEG), PEGylation, has been considered a useful tool to improve drug-like properties of novel small molecules and biologics in drug discovery. PEG40 or 40 kDa PEG is a double-branched PEG, routinely employed to improve the pharmacokinetics (PK) of therapeutics, including successful marketed products such as Pegasys® and Omontys®. However, less is known about the extent of contribution of PEG40 to the overall PK of the PEGylated product.

Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2.

A search for structurally diversified Tyk2 JH2 ligands from (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the -methyl triazolyl moiety in . The X-ray co-crystal structure of an early lead () revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate.

Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as with improved potency and selectivity.

Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity.

Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain.

Pharmacokinetics of 40 kDa PEG in rodents using high-field NMR spectroscopy.

Conjugation of macromolecular drugs to polyethylene glycol (PEG) improves their therapeutic potential by reducing their rate of degradation, thereby extending the drugs half life. As a substantial component of the drug, it is necessary to measure the pharmacokinetic (PK) characteristics of PEG in vivo. A quantitative NMR-based method was developed and successfully applied to measuring double-branched polyethylene glycol 40 kDa (PEG40) in serum samples, enabling determination of PK parameters of PEG40 in preclinical species.

Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape.

A cross-industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering.

Selective I Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide.

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent I current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors.

Antibody Drug-Target Engagement Measurement in Tissue Using Quantitative Affinity Extraction Liquid Chromatography-Mass Spectrometry: Method Development and Qualification.

We demonstrate a novel strategy using affinity extraction (AE) LC-MS to directly measure drug exposure and target engagement, two critical pharmacological questions, with a single assay. The assay measures total drug and target concentration at the site of therapeutic action, as well as the amount of target bound to drug. The case study presented applies the strategy to measure drug engagement of a membrane bound receptor (CD40) that is critical to immune regulation in colon biopsies collected from monkey dosed with an anti-CD40 antibody.

Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent I Kur Inhibitor.

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.

LC-MS/MS multiplexed assay for the quantitation of a therapeutic protein BMS-986089 and the target protein Myostatin.

Background: Therapeutic protein discovery study highlights the need for the development of quantitative bioanalytical methods for determining the levels of both the therapeutic protein and the target protein, as well.

Results: For the quantitation of BMS-986089, both accuracy (99-103%) and precision (2.4-12%) were obtained for the analysis of the surrogate peptide (ITYGGNSPVQEFTVPGR), in addition to the accuracy (100-108%) and precision (0.

Pseudosaccharin amines as potent and selective KV1.5 blockers.

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.

Development and characterization of a free therapeutic ligand binding assay with assistance from kinetics modeling.

Bioanalytical data from early human studies conducted in normal volunteers are often used for building pharmacokinetic/pharmacodynamic models that can predict outcomes of future studies in diseased patients. Thus, it is important to develop and validate reliable and accurate bioanalytical assays that instill confidence that the intended therapeutic species (total or free) are being measured. Assays quantifying the free therapeutic species, the partially bound (for multivalent therapeutics) and unbound species, require much more characterization than assays that quantify the total therapeutic species.

Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119.

G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes.

Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir.

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described.

Factors influencing magnitude and duration of target inhibition following antibody therapy: implications in drug discovery and development.

Antibodies or antibody-related fusion proteins binding to soluble antigens in plasma form an important subclass of approved therapeutics. Pharmaceutical companies are constantly trying to accelerate the pace of drug discovery and development of these antibodies and identify superior candidates in face of significant attrition rates. Understanding the interplay between drug- and target-related factors on magnitude and duration of target inhibition is imperative for successful advancement of these therapeutics.

Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19.

Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC₅₀ values were greater than 40 μM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC₅₀ = ∼8 μM) and esomeprazole with CYP2C8 (IC₅₀ = 31 μM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC₅₀ ratio, 2.

Quantitative relationship between rifampicin exposure and induction of Cyp3a11 in SXR humanized mice: extrapolation to human CYP3A4 induction potential.

The SXR humanized mouse model was used to quantitatively assess an in vivo induction response of the human PXR agonist, rifampicin. Three days of rifampicin treatment increased RNA expression and microsomal enzyme activity of CYP3A11, as well as significantly reduced triazolam plasma exposure. These results indicate that the humanized SXR mouse can be used as a model to predict human CYP3A4 induction and the resulting pharmacokinetic changes of CYP3A4 substrates in humans.

Effects of methylprednisolone and its liver-targeted dextran prodrug on ischemia-reperfusion injury in a rat liver transplantation model.

Purpose: To evaluate the effectiveness of a liver-targeted dextran prodrug (DMP) of methylprednisolone (MP) in cold preservation-warm reperfusion injury associated with liver transplantation.

Methods: The effects of donor pretreatment with single 5 mg/kg doses of MP or DMP on ischemia-reperfusion damage to the liver were studied after 8 or 24 h of cold preservation in both isolated perfused rat liver (IPRL) and syngeneic orthotopic rat liver transplantation (OLT) models.

Results: In IPRL studies, donor pretreatment with DMP, and to a lesser degree MP, significantly improved the uptake of hyaluronic acid (HA), a marker of endothelial cell function, following 8 h of cold preservation.

Attenuation of acute rejection in a rat liver transplantation model by a liver-targeted dextran prodrug of methylprednisolone.

Background: The use of methylprednisolone (MP) and other corticosteroids for the treatment of acute liver allograft rejection is associated with severe toxicities in nontarget tissues. Therefore, selective delivery of MP to the liver may improve its efficacy and alleviate its side effects. We investigated the effects of a novel liver-targeted dextran prodrug of MP (DMP) in an orthotopic rat liver transplantation (OLT) model.

Effects of duration of ischemia and donor pretreatment with methylprednisolone or its macromolecular prodrug on the disposition of indocyanine green in cold-preserved rat livers.

Purpose: Cold preservation of the liver before transplantation may change uptake and excretory functions of hepatocytes. We hypothesized that an increase in the duration of preservation would result in a progressive decrease in the hepatic uptake and/or biliary excretion of indocyanine green (ICG), which would be attenuated by pharmacologic interventions.

Methods: Donor rats (n = 40) were administered saline (control) or single 5 mg/kg doses of methylprednisolone (MP) or its liver-targeted prodrug (DMP) 2 h prior to liver harvest.