Real-life experience with hazelnut oral immunotherapy.

BACKGROUND: Hazelnut oral immunotherapy (H-OIT), a promising alternative to hazelnut-free diet for patients with hazelnut allergy, has not been extensively studied. OBJECTIVE: To investigate the effectiveness of H-OIT for children with hazelnut allergy. METHODS: Retrospective medical record review of children treated by H-OIT in the University Hospital of Lyon (France) was reported. Clinical and laboratory data were collected, and the satisfaction of the children treated by H-OIT was evaluated using a questionnaire. RESULTS: A total of 70 patients treated by H-OIT for an immunoglobulin E-mediated hazelnut allergy (94.3%) or an immunoglobulin E sensitization to hazelnut (5.7%) were included. Among these, 22.9% entered the maintenance phase at 1-year consultation and 60.0% entered the maintenance phase during the study period. At home, 57.1% of the patients experienced at least 1 adverse effect and 2.9% experienced severe systemic allergic reactions. Among the 212 oral food challenges conducted at hospital, 3.3% led to severe systemic reactions and epinephrine was used 4 times. A total of 21.4% of children discontinued treatment; aversion to hazelnut was the main reason. There were 42 children aged 8 years or more and their parents who answered the questionnaire. H-OIT was considered a strain for children but effective and was recommended to other children with allergy. CONCLUSION: H-OIT seemed to be effective and well accepted by children. This is counterbalanced by a high rate of H-OIT discontinuation, mainly owing to aversion to hazelnut, and an important rate of adverse reactions, which are however mostly mild. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04841850.

Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014.

The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).

The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase.

We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.

Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR.

A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.

4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.

Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.

Novel alkoxybenzamide inhibitors of poly(ADP-ribose) polymerase.

We have previously described poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a substituted benzyl-phthalazinone scaffold. As an alternative chemical template, a novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors.

Potent and selective xanthine-based inhibitors of phosphodiesterase 5.

Inhibitors of PDE5 are useful therapeutic agents for treatment of erectile dysfunction. A series of novel xanthine derivatives has been identified as potent inhibitors of PDE5, with good levels of selectivity against other PDE isoforms, including PDE6. Studies in the dog indicate excellent oral bioavailability for compound 21.

Phthalazinones. Part 1: The design and synthesis of a novel series of potent inhibitors of poly(ADP-ribose)polymerase.

Screening of the Maybridge compound collection identified 4-arylphthalazinones as micromolar inhibitors of PARP-1 catalytic activity. Subsequent optimisation of both inhibitory activity and metabolic stability led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-ones with low nanomolar, cellular activity as PARP-1 inhibitors and promising metabolic stability in vitro.

8-Aryl xanthines potent inhibitors of phosphodiesterase 5.

In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.