Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa.

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold.

Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.

Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge.

Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency.

Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle.

Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.

A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors.

Novel phenylalanine derived diamides as Factor XIa inhibitors.

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.

Late-onset anaphylaxis after ingestion of Bacillus Subtilis-fermented soybeans (Natto): clinical review of 7 patients.

Background: Allergic reactions after ingestion of fermented soybeans have rarely been reported. Fermented soybeans were recently reported to be a causative food of IgE-mediated, late-onset anaphylaxis without early phase responses. The objectives of our study are to clarify the clinical and laboratory features and to characterize the allergens in allergy due to fermented soybeans.

Safety of selective cyclooxygenase-2 inhibitors and a basic non-steroidal anti-inflammatory drug (NSAID) in Japanese patients with NSAID-induced urticaria and/or angioedema: Comparison of meloxicam, etodolac and tiaramide.

The identification of a safe and reliable alternative for patients with non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema is a frequent problem for dermatologists and other practitioners. Cyclooxygenase-2 (COX-2) inhibitors have been reported to be safe for NSAID-intolerant patients from the US and Europe but not all of them have yet been approved for use in Japan. It was our objective to investigate the clinical manifestations of oral NSAID challenges in Japanese patients with histories of urticaria and/or angioedema after the intake of NSAIDs and to find safe alternative drugs, including COX-2 inhibitors and a basic anti-inflammatory drug.

A pediatric case of anaphylaxis caused by matsutake mushroom (Tricholoma matsutake) ingestion.

Background: Anaphylaxis is one of the severest forms of allergic diseases. Some kinds of mushroom are known as causative allergens in food anaphylaxis. Matsutake mushroom (Tricholoma matsutake) is a typical edible mushroom available in autumn in Japan.

Multiple chemical sensitivities following intolerance to azo dye in sweets in a 5-year-old girl.

Background: Cases of multiple chemical sensitivities (MCS) have been reported predominantly in adult patients, but pediatric cases have rarely been reported.

Methods: We present a 5-year-old girl who suffered from recurrent reactions accompanied by urticaria, angioedema, headaches, dyspnea, loss of consciousness, and abdominal pain that were not eradicated, but were instead exacerbated, by various treatments with antihistamines and intravenous corticosteroids. Her diet diary revealed that symptoms occurred after ingestion of colorful sweets such as candies and jellybeans.

[Enhancement of nonsteroidal, anti-inflammatory drugs and preventive effect of antihistamines and disodium cromoglycate on wheat allergy].

Background: Aspirin has been known to be an enhancer to wheat allergy, including wheat-dependent, exercise-induced anaphylaxis.

Objective: To investigate whether nonsteroidal, anti-inflammatory drugs (NSAIDs) other than aspirin would enhance allergic reactions after wheat ingestion and whether antihistamines and disodium cromoglycate would prevent these reactions.

Methods: Seven cases, whose reactions after wheat ingestion were enhanced by aspirin on challenge tests, were enrolled.

[Oral allergy syndrome due to cashew nuts in the patient without pollinosis].

A 26-year-old woman felt tingling on her tongue and itching both in the throat and on the face immediately after she put a cashew nut on her tongue. She had a history of atopic dermatitis and bronchial asthma, but not of pollinosis. CAP-FEIA and skin prick test (SPT) were positive for cashew nuts.

[Wheat anaphylaxis enhanced by administration of acetylsalicylic acid or by exercise].

A 23-year-old woman experienced generalized urticaria and loss of consciousness during walking after ingestion of wheat. Skin prick test and CAP-RAST were positive for gluten. An oral challenge test using 100g wheat was positive without exercise.

Late-onset anaphylaxis to fermented soybeans: the first confirmation of food-induced, late-onset anaphylaxis by provocation test.

Background: Late-onset anaphylactic reactions without early-phase reactions are rarely reported. The hypothesized mechanism of late-onset anaphylaxis to fermented soybeans is delayed absorption or release into the bowel rather than an immunologic phenomenon.

Objectives: To investigate the mechanisms of late-onset anaphylaxis to fermented soybeans in 2 patients and to characterize the allergens involved in anaphylaxis caused by fermented soybeans.

[A case of latex allergy suspected drug allergy].

A 30-year-old female with paroxysmal supraventricular tachycardia (PSVT) underwent catheter ablation. About 30 minutes later, urticaria and dyspnea occurred suddenly. Blood pressure decreased to 62/41 mmHg, and she fell into the state of anaphylactic shock.

Identification of the IgE-binding epitope in omega-5 gliadin, a major allergen in wheat-dependent exercise-induced anaphylaxis.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a severe IgE-mediated allergic reaction provoked by the combination of wheat-ingestion with intensive physical exercise over the next few hours. Among wheat proteins, omega-5 gliadin, which is one of the components of fast omega-gliadin, has been reported as a major allergen in the anaphylaxis. In this study, we detected IgE-binding epitopes within the primary sequence of omega-5 gliadin using arrays of overlapping peptides synthesized on derivatized cellulose membranes.

Neuropeptides concentrations in the skin of a murine (NC/Nga mice) model of atopic dermatitis.

Background: It has been reported that the expression of neuropeptides (NPs), and the density and structure of peripheral nerves in atopic dermatitis (AD) are different from those in normal skin.

Objective: We investigated the role of NPs, in the development of AD with quantitative study of substance P (SP) and calcitonin gene-related peptide (CGRP) in the skin of AD-model mice.

Methods: We measured the NPs in the skin of mice (NC/Nga as AD-model mice, BALB/c and C57BL/6 as control) by enzyme-linked immunosorbentassay (ELISA).

Significance of carbohydrate epitopes in a latex allergen with beta-1,3-glucanase activity.

Background: One of the latex allergens, Hev b 2, has beta-1,3-glucanase activity. The entire sequence of this allergen is already known. There is one potential N-glycosylation site in this molecule ((27)Asn).

Food-dependent exercise-induced anaphylaxis: influence of concurrent aspirin administration on skin testing and provocation.

Background: Provocation tests in patients with food-dependent exercise-induced anaphylaxis (FDEIA) are often negative, even after a sufficient quantity of the implicated food and exercise have been taken.

Objectives: To investigate the effect of aspirin in provocation tests and in skin prick testing (SPT) of patients with FDEIA. Gluten as a major allergen in wheat-dependent FDEIA was also investigated.

The necessity for dual food intake to provoke food-dependent exercise-induced anaphylaxis (FEIAn): a case report of FEIAn with simultaneous intake of wheat and umeboshi.

Background: Food-dependent exercised-induced anaphylaxis (FEIAn) is classified among the physical allergies. Many different food allergens have been reported, but the pathophysiology of FEIAn remains unknown. Furthermore, provocation tests with a suspected food do not always succeed in patients with FEIAn.

Digestibility of allergens extracted from natural rubber latex and vegetable foods.

Background: Several cross-reactive allergens are now known to be involved in the defense responses of higher plants. Such proteins are drawing the attention of plant breeders because of their antimicrobial or stress-alleviating activities. Plants genetically modified to express defense-related proteins are being developed.

[Usefulness of hypoallergenic rice (AFT-R 1) and analysis of the salt insoluble rice allergen molecule].

An involvement of rice allergy in development and exacerbation of recalcitrant atopic dermatitis (AD) has been suggested in some cases, and it has been also known that elimination diet of rice results in improvement of AD and reduction of the doses of steroid ointment and anti-allergic drugs used for the treatment. We prepared the hypoallergenic rice grain, AFT-R 1 (Allergen-free Technology Lab. Inc.