Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.

AST-3424 is a novel and highly tumor-selective prodrug. AST-3424 is activated by AKR1C3 to release a toxic bis-alkylating moiety, AST 2660. In this study, we have investigated the essential role of DNA repair in AST-3424 mediated pharmacological activities in vitro and in vivo.

HLA-DRB5 promotes immune thrombocytopenia via activating CD8 T cells.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by a low platelet (PLT) count and a high risk of bleeding, the clinical treatment for which still needs to be upgraded. Based on the critical role of human leukocyte antigen class II heterodimer β5 (HLA-DRB5) in immune system, we herein investigated its effect on ITP. ITP murine models were established by the injection of guinea pig anti-mouse platelet serum (GP-APS), and the PLT of mouse peripheral blood was counted during the modeling.

HLA-DRB5 Overexpression Promotes Platelet Reduction in Immune Thrombocytopenia Mice Model by Facilitating MHC-II-Mediated Antigen Presentation.

Introduction: Major histocompatibility complex II (MHC-II)-mediated antigen presentation contributes to the pathogenesis of immune thrombocytopenia (ITP). Human leukocyte antigen (HLA)-DRB5 is an MHC-II molecule and this study aims to investigate its role and mechanisms in ITP development.

Methods: Guinea pig anti-mouse platelet (PLT) serum-induced ITP mice received tail vein injection of HLA-DRB5 overexpressing adenoviral vector/immune receptor expressed on myeloid cells-1 (IREM-1) monoclonal antibody (mAb).

Increased serum levels of high-mobility group box 1 protein and the location characteristics in the patients of intracranial aneurysms.

Objective: Inflammation-related factors play a crucial role in intracranial aneurysms (IA) initiation, progression, and rupture. High mobility group box 1 (HMGB-1) serves as an alarm to drive the pathogenesis of the inflammatory disease. This study aimed to evaluate the role of HMGB-1 in IA and explore the correlation with other inflammatory-related factors.

Preoperative Fibrinogen Levels and Function as Predictive Factors for Acute Bleeding in the Hematoma Cavity After Burr Hole Drainage in Patients with CSDH.

Objective: Burr hole drainage (BHD) is the primary surgical intervention for managing chronic subdural hematoma (CSDH). However, it can lead to postoperative complications such as acute bleeding within the hematoma cavity and hematoma recurrence. The objective of this study is to identify the risk factors for these complications and develop a predictive model for acute hematoma cavity bleeding after BHD in patients with CSDH.

Right-to-Left Displacement of an Airgun Lead Bullet after Transorbital Entry into the Skull Complicated by Posttraumatic Epilepsy : A Case Report.

Penetrating head injury is a serious open cranial injury. In civilians, it is often caused by non-missile, low velocity flying objects that penetrate the skull through a weak cranial structure, forming intracranial foreign bodies. The intracranial foreign body can be displaced due to its special quality, shape, and location.

Etiologies of Hospitalized Acute Bronchiolitis in Children 2 Years of Age and Younger: A 3 Years' Study During a Epidemic.

In recent years, the incidence of infection in infants and young children has been increasing. Multiple studies have suggested that may be one of the pathogens of bronchiolitis in infants and young children. However, the prevalence and clinic characteristic of in bronchiolitis is controversial.

Virus Coinfection is a Predictor of Radiologically Confirmed Pneumonia in Children with Bordetella pertussis Infection.

Introduction: This study aimed to prospectively investigate the burden of pertussis in southeast Chinese children hospitalized with lower respiratory tract infection (LRTI) during a pertussis outbreak and to compare the outcomes of Bordetella pertussis infection with or without virus coinfections.

Methods: Children < 24 months of age hospitalized with LRTI were prospectively enrolled from January 2017 to December 2019. Demographic and clinical information were recorded, and respiratory tract samples were tested for the presence of B.

An Effective and Simple Way to Establish Elastase-Induced Middle Carotid Artery Fusiform Aneurysms in Rabbits.

Objective: Elastase-induced aneurysms in rabbits have been proposed as a preclinical tool for device development, but there is still much deficiency in those aneurismal models. So we need to explore the efficient and convenient animal models for the investigation of intracranial aneurysms. Then, we compared and analyzed three methods of elastase-induced carotid artery aneurysms in rabbits and aimed to find a simple, effective, and reproducible method for creating elastase-induced aneurysms.

The active participation of p22phox-214T/C in the formation of intracranial aneurysm and the suppressive potential of edaravone.

Oxidative stress reactions play an important role in the pathogenesis of intracranial aneurysm (IA). p22phox is involved in the oxidative stress reaction, and it is a critical subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The present study investigated the association of genetic variants within the gene encoding p22phox‑214T/C with IA.

Association between nonsteroidal anti-inflammatory drugs use and risk of central nervous system tumors: a dose-response meta analysis.

Although studies have examined the association between nonsteroidal anti-inflammatory drugs (NSAIDs) use and central nervous system (CNS) tumors risk, the results are inconclusive. Here, we conducted a dose-response meta-analysis in order to investigate the correlation between NSAIDs use and CNS tumors risk. Up to July 2017, 12 studies were included in current meta-analysis.

Benzodiazepine drug use and cancer risk: a dose-response meta analysis of prospective cohort studies.

Conflicting results identifying the relationship between benzodiazepine drug use and cancer risk. Therefore, we conducted a dose-response meta-analysis of prospective cohort studies to clarify and quantitative assessed the relationship between benzodiazepine drug use and cancer risk. Up to July 2017, 22 original publications were included in current meta-analysis.

Association of TNF-α-3959T/C Gene Polymorphisms in the Chinese Population with Intracranial Aneurysms.

Recent studies have demonstrated that cytokines play an important role in the pathogenesis of intracranial aneurysm (IA). Tumor necrosis factor-α (TNF-α) is an important proinflammatory cytokine, which was shown to influence the development of IA, but there is no research data from China. Hence, the purpose of this study was to explore the relationship between TNF-α polymorphisms and IA in China.

Discovery of the imidazole-derived GPR40 agonist AM-3189.

As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.

Prodrug AST-003 Improves the Therapeutic Index of the Multi-Targeted Tyrosine Kinase Inhibitor Sunitinib.

Patients have responded well to the multi-targeted tyrosine kinase inhibitor (TKI) Sunitinib in the clinic. But the severe toxic side effects associated with Sunitinib limit its therapeutic index. To improve the therapeutic index of Sunitinib, a prodrug strategy was employed to modify Sunitinib.

Improving the Pharmacokinetics of GPR40/FFA1 Full Agonists.

We recently reported the discovery of a potent GPR40 full agonist AM-1638 (1). Herein, we describe our efforts in improving the drug-like properties of the full agonists through the systematic introduction of polar groups in the C-, D-, and A-rings. This led to the discovery of new GPR40 full agonists with significantly improved pharmacokinetic propeties.

Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile.

Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD(2) receptors CRTH2 and DP.

Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI).

Discovery and optimization of arylsulfonyl 3-(pyridin-2-yloxy)anilines as novel GPR119 agonists.

We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.

Optimization of phenylacetic acid derivatives for balanced CRTH2 and DP dual antagonists.

Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15.

Discovery of potent and specific CXCR3 antagonists.

The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay.

Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.

Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2.

Discovery of non-glucoside SGLT2 inhibitors.

A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors.

Optimization of a series of quinazolinone-derived antagonists of CXCR3.

The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties.

Design and optimization of imidazole derivatives as potent CXCR3 antagonists.

A series of imidazole derivatives have been designed and optimized for CXCR3 antagonism, pharmacokinetic properties, and reduced formation of glutathione conjugates. Our efforts led to the discovery of potent CXCR3 antagonists with good pharmacokinetic properties. These compounds are useful tools for in vivo studies of CXCR3 function.