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Discovery of potent, orally bioavailable in vivo efficacious antagonists of the TLR7/8 pathway
No full textAntagonism of the Toll-like receptors (TLRs) 7 and TLR8 has been hypothesized to be beneficial to patients suffering from autoimmune conditions. A phenotypic screen for small molecule antagonists of TLR7/8 was carried out in a murine P4H1 cell line. Compound 1 was identified as a hit that showed antagonistic activity on TLR7 and TLR8 but not TLR9, as shown on human peripheral blood mononuclear cells (hPBMCs). It was functionally cross reactive with mouse TLR7 but lacked oral exposure and had only modest potency. Chemical optimization resulted in 2, which showed in vivo efficacy following intraperitoneal administration. Further optimization resulted in 8 which had excellent in vitro activity, exposure and in vivo activity. Additional work to improve physical properties resulted in 15, an advanced lead that had favorable in vitro and exposure properties. It was further demonstrated that activity of the series tracked with binding to the extracellular domain of TLR7 implicating that the target of this series are endosomal TLRs rather than downstream signaling pathways
Evaluation of 5H-thiazolo[3,2-alpha]pyrimidin-5-ones as potential GluN2A PET tracers.
No full textWe describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on 5H-thiazolo[3,2-]pyrimidin-5-one scaffold. Metabolic stability and overall properties could be optimized satisfactorily, while binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)- methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one ([18F]7b) as a radioligand providing good quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([3H]11a), which was used for the successful development of a radioligand binding assay. These are valuable new tools for the study of GluN2A-containing NMDA receptors, and for the optimization of allosteric modulators binding to the pharmacophore located at the dimer interface of the GluN1−GluN2A ligand-binding domain
Novel advances in biotransformation and bioactivation research—2019 year in review*
No full textBiotransformation is one of the main mechanisms used by the body to eliminate drugs. As drug molecules become more complicated, the involvement of drug metabolizing enzymes increases beyond those that are typically studied, such as the cytochrome P450 enzymes. In this review, we try to capture the many outstanding articles that were published in the past year in the field of biotransformation (see Table 1). We have divided the articles into two categories of (1) metabolites and drug metabolizing enzymes, and (2) bioactivation and safety. This annual review is the fifth of its kind since 2016 (Baillie et al. 2016; Khojasteh et al. 2017, 2018, 2019). This effort in itself also continues to evolve. We have followed the same format we used in previous years in terms of the selection of articles and the authoring of each section. I am pleased of the continued support of Rietjens, Miller, Zhang, Driscoll and Mitra to this review. We would like to welcome Klarissa D. Jackson as a new author for this year’s issue. We strive to maintain a balance of authors from academic and industry settings. We would be pleased to hear your opinions of our commentary, and we extend an invitation to anyone who would like to contribute to a future edition of this review. Cyrus Khojasteh, on behalf of the authors
New Perspectives on Drug-Induced Liver Injury Risk Assessment of Acyl Glucuronides
No full textthe Novartis internal working group came up with an internal guidance. We would like to publish this guidance together with external collaborators.
Therefore , we seek OAK clearance on the guidance to share it with external collaborators from AZ, UCB and University of Basel.
No current running Novartis Projects are mentioned in the guidance
Introducing the concept of virtual control groups into preclinical toxicology testing.
No full textSharing legacy data from in vivo toxicity studies offers the opportunity to analyze the variability of control groups stratified for strain, age, duration of study, vehicle and other experimental conditions. Historical animal control group data may lead to a repository, which could be used to construct virtual control groups (VCGs) for toxicity studies. VCGs are an established concept in clinical trials, but the idea of replacing living beings with virtual data sets has so far not been introduced into the design of regulatory animal studies. The use of VCGs has the potential of a 25% reduction in animal use by replacing the control group animals with existing randomized data sets. Prerequisites for such an approach are the availability of large and well-structured control data sets as well as thorough statistical evaluations. the foundation of data sharing has been laid within the Innovative Medicines Initiatives projects eTOX and eTRANSAFE. For a proof of principle participating companies have started to collect control group data for subacute (4-week) GLP studies with Wistar rats (the strain preferentially used in Europe) and are characterizing these data for its variability. In a second step, the control group data will be shared among the companies and cross-company variability will be investigated. In a third step, a set of studies will be analyzed to assess whether the use of VCG data would have influenced the outcome of the study compared to the real control group
Evaluation of Absolute Oral Bioavailability and Bioequivalence of Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, in Healthy Subjects
No full textRibociclib, a selective and potent cyclin-dependent kinase 4/6 inhibitor, has demonstrated safety and efficacy in combination with endocrine therapy in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer. In 2 open-label crossover studies in healthy participants, the absolute bioavailability of a single oral dose of a ribociclib 600-mg tablet (n = 16) was compared with a single intravenous ribociclib infusion of 150 mg (n = 16), and the bioequivalence of a ribociclib 600-mg tablet (n = 31) and a ribociclib 600-mg capsule (n = 31) was evaluated. The pharmacokinetics of ribociclib and its major metabolite, LEQ803, were assessed in both studies. The oral bioavailability of the 600-mg ribociclib tablet was 65.8% (90% confidence interval [CI], 59.1-73.2%). The geometric mean systemic clearance of ribociclib was moderate (40.2 L/h; 27.4% intersubject variability [CV%]) compared with hepatic blood flow, and the geometric mean volume of distribution was high (979 L; 25.2 CV%). LEQ803-to-ribociclib metabolic ratios were 0.198 for the oral administration and 0.125 for intravenous infusion. Bioequivalence of the tablet and capsule formulations was demonstrated for ribociclib. The geometric mean ratios of maximum concentration and area under the curve from time 0 to last quantifiable concentration and to infinity were 1.01, 1.00, and 0.937, respectively, within the predefined bioequivalence range of 0.80 to 1.25. The median time to reach maximum concentration was 3 hours with both formulations. No serious adverse events were observed in either study
Accelerating the Development of Novel Technologies and Tools for the Subcutaneous Delivery of Biotherapeutics
No full textSubcutaneous (SC) delivery of biotherapeutics is an effective and well-tolerated route of administration that offers notable advantages over intravenous (IV) administration. This notwithstanding, there remain critical development issues and knowledge gaps in SC drug delivery. To articulate and address these issues, the SC Drug Delivery and Development Consortium was convened in 2018 as a pre-competitive collaboration of industry experts in drug delivery, device development and commercialization. In this review, we outline the Consortium’s vision and mission in advancing the development of patient-centered biotherapeutics and establishing a collaborative organization that facilitates open sharing of information and gives voice to diverse viewpoints from SC experts across industries and disciplines. Additionally, we describe the current landscape and challenges associated with SC administration of therapeutic proteins and offer insights into potential solutions to these challenges within the context of 8 problem statements developed by the Consortium to highlight key gaps, unmet needs and actionable issues. Current and future opportunities to accelerate progress in the field through technological advances and the development of drug delivery tools are also discussed
Understanding the adsorption and potential tear film stability properties of recombinant human lubricin and bovine submaxillary mucins in an in vitro tear film model
No full textThe wetting and adsorption properties for two glycoproteins, recombinant human lubricin and bovine submaxillary mucins (BSM) were evaluated on hydrophilic and hydrophobic glass dome surfaces in a simplified in vitro tear film model. We show that both recombinant human lubricin (rh-lubricin) and BSM solutions render surfaces hydrophilic and when the fluid films reach 500 nm or less, the fluids resist evaporation-driven breakup through a volumetric flux across the surface, which we believe is due to evaporation-driven solutocapillary flows. rh-Lubricin was able to maintain a wet film without spontaneous breakup for longer periods of time than BSM at lower concentrations, which we attribute to differences in adsorption properties, measured by QCM-D, that result from surface charge and structural differences (confirmed by zeta potential, DLS, and SAXS measurements)
Sustainable ppm Palladium-Catalyzed Tsuji-Trost Reactions Enabled by Aqueous Micellar Catalysis
No full textPalladium-catalyzed allylic substitution, or “Tsuji-Trost” reactions, can be run under micellar catalysis conditions featuring not only chemistry in water, but also numerous combinations of reaction partners that require low levels of palladium, typically on the order of 1000 ppm (0.1 mol %). These couplings are further characterized by especially mild conditions, leading to a number of cases not previously reported in an aqueous micellar medium. Inclusion of diverse nucleophiles, such as N-H heterocycles, alcohols, dicarbonyl compounds, and sulfonamides is described. Intramolecular cyclizations further illustrate the broad utility of this process. In addition to recycling studies, a multi-gram scale example is reported, indicative of the prospects for scale up
Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis
No full textThe lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery