Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.
Sixty-six participants (33 males, 33 females) with microcephaly (MC), age range from 2 to 19 years old, were evaluated. MC was classified pathogenetically into isolated MC (IMC) and multiple MC (MMC) and classified etiologically into primary MC (PMC) and secondary MC (SMC). Both IMC and MMC were further classified. Overall prevalence of epilepsy was 40.9%. Furthermore, there was a significantly higher prevalence of epilepsy in males. Main seizure type was generalized tonic-clonic seizures. Generally, learning disability (LD) was diagnosed in 93.9% and profound LD was evident in 43.9% of participants. There was an inverse correlation between severity of epilepsy and IQ but a positive correlation between severity of epilepsy and degree of LD. Differences in the success rate between monotherapy and polytherapy or response to antiepileptic drugs were not observed. Results suggest that epilepsy may be associated with the lower cognitive ability of the participants with microcephaly. The pathogenetic classification proposed is of value in delineating the prevalence of epilepsy and LD in the different varieties of MC as compared with the etiological classification.
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