Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates.

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by , discovered earlier as metallo-beta-lactamase inhibitors, was selected for virtual screening.

Characterization of the Onset, Progression, and Reversibility of Morphological Changes in Mouse Lung after Pharmacological Inhibition of Leucine-Rich Kinase 2 Kinase Activity.

Gain-of-function mutations in leucine-rich kinase 2 (LRRK2) are associated with increased incidence of Parkinson disease (PD); thus, pharmacological inhibition of LRRK2 kinase activity is postulated as a disease-modifying treatment of PD. Histomorphological changes in lungs of nonhuman primates (NHPs) treated with small-molecule LRRK2 kinase inhibitors have brought the safety of this treatment approach into question. Although it remains unclear how LRRK2 kinase inhibition affects the lung, continued studies in NHPs prove to be both cost- and resource-prohibitive.

Is there a role for the no observed adverse effect level in safety pharmacology?

In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society.

Twenty years of safety pharmacology model validation and the wider implications of this to drug discovery.

This editorial summarizes the content of the current themed issue of J Pharm Tox Methods derived from the 2019 Annual Safety Pharmacology Society (SPS) meeting held in Barcelona, Spain, and reflects on 20 years of innovation in the elaboration of methods for evaluating adversity, particularly during the nonclinical research phase. Given the success of safety pharmacology (SP) in the last 20 years, we propose that the rubric for SP method invention and validation be examined in more detail to explore whether it may have wider relevance to the drug discovery process. Articles arising from the Barcelona meeting are summarized here.

Abuse liability assessment for biologic drugs - All molecules are not created equal.

The development of novel drug candidates involves the thorough evaluation of potential efficacy and safety. To facilitate the safety assessment in light of global increases in prescription drug misuse/abuse, health authorities have developed guidance documents which provide a framework for evaluating the abuse liability of candidate therapeutics. The guidances do not distinguish between small molecules and biologics/biotherapeutics; however, there are key differences between these classes of therapeutics which are important drivers of concern for abuse.

The Safety Pharmacology Society salary survey.

Introduction: Safety pharmacology is a growing discipline with scientists broadly distributed across international geographical regions. This electronic salary survey is the first to be distributed amongst the entire Safety Pharmacology Society (SPS) membership. An electronic survey was sent to all members of the Society.

Safety pharmacology investigations on the nervous system: An industry survey.

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees).

EEG in non-clinical drug safety assessments: Current and emerging considerations.

Electroencephalogram (EEG) data in nonclinical species can play a critical role in the successful evaluation of a compound during drug development, particularly in the evaluation of seizure potential and for monitoring changes in sleep. Yet, while non-invasive electrocardiogram (ECG) monitoring is commonly included in preclinical safety studies, pre-dose or post-dose EEG assessments are not. Industry practices as they relate to preclinical seizure liability and sleep assessments are not well characterized and the extent of preclinical EEG testing varies between organizations.

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of familial and sporadic Parkinson's disease (PD). That the most prevalent mutation, G2019S, leads to increased kinase activity has led to a concerted effort to identify LRRK2 kinase inhibitors as a potential disease-modifying therapy for PD. An internal medicinal chemistry effort identified several potent and highly selective compounds with favorable drug-like properties.

Assessment of seizure liability of Org 306039, a 5-HT2c agonist, using hippocampal brain slice and rodent EEG telemetry.

Introduction: Evaluation of the seizure potential for a CNS-targeted pharmaceutical compound before it is administered to humans is an important part of development. The current in vitro and in vivo studies were undertaken to characterize the seizure potential of the potent and selective 5-HT2c agonist Org 306039.

Methods: Rat hippocampal slices (n=5) were prepared and Org 306039 was applied over a concentration range of 0-1000μM.

Comparison of methods for analysis of functional observation battery (FOB) data.

Introduction: Different methods for the analysis of behavioral observation data were compared to evaluate how the interpretation of a data set may depend on the analysis method employed.

Methods: Three methods of analysis were used to evaluate the same four sets of rodent behavioral FOB data: (1) evaluation by a trained behavioral toxicologist (ToxRev); (2) Kruskal-Wallis statistical analysis of variance for nonparametric data followed by Wilcoxon pairwise tests (KW) and (3) Cochran-Mantel-Haenszel statistical analysis of variance for nonparametric data followed by Wilcoxon pairwise tests (CMH). The FOB consisted of 9 behavioral, 10 neurologic and 7 autonomic parameters that were evaluated following administration of either vehicle or diazepam (1 or 4 mg/kg; 1, 2 or 5 mg/kg) to male and female rats.

Benchmarking safety pharmacology regulatory packages and best practice.

Introduction: The objectives of this survey were to obtain a global information update regarding current industry perspectives that describe Safety Pharmacology programs as they relate to the ICH S7A and S7B regulatory guidelines but also to obtain a broader perspective of other practises practices in the field currently used by companies. Preliminary findings were presented at the 7th Annual Meeting of the Safety Pharmacology Society (SPS) (Edinburgh, Scotland, Sept 19-21, 2007).

Methods: The survey was distributed by the SPS to 125 pharmaceutical companies.

Validation of a motor activity system by a robotically controlled vehicle and using standard reference compounds.

Introduction: A series of experiments were undertaken to evaluate the accuracy, precision, specificity, and sensitivity of an automated, infrared photo beam-based open field motor activity system, the MotorMonitor v. 4.01, Hamilton-Kinder, LLC, for use in a good laboratory practices (GLP) Safety Pharmacology laboratory.