Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases.

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.

HACCP Models for Quality Control of Entree Production in Foodservice Systems.

Quality control is a major management function in foodservice systems. Quality is defined as a composite of microbiological, nutritional, and sensory attributes. The Hazard Analysis Critical Control Point (HACCP) concept is a preventive approach to quality control, emphasizing microbiological control and identifying process stages where loss of control could present a food safety risk. Applying this concept, which has been implemented in the frozen food processing industry. HACCP models were developed for quality control of entree production in conventional, cook/chill, and cook/freeze foodservice systems in three phases: identification of control points using flow diagrams, identification of critical control points, and establishment of monitors for control. Time-temperature was a critical control point throughout entree production in each of the models; parameters were established for time-temperature and continuous surveillance of time-temperature was the monitor for control. Equipment and personnel sanitation are critical control points which should be monitored using standards established by the foodservice system. Implementation of the HACCP system is recommended for foodservice operations. However, standards and monitors for control of critical control points must be established for each operation and based on their own system objectives, resources, and constraints.