Benzodiazepines (BZD) are commonly used in the treatment of mental disorders such as anxiety disorders, schizophrenia, depression and neuropathic pain which affect over 18% of the US population. However, many patients respond poorly to the classical BZD’s by suffering a variety of adverse effects including sedation, ataxia, tolerance, and addiction. Hz-166 (Zeilhofer et al.), a previously characterized 1,4-Benzodiazepine was identified as an αlpha 2/αlpha 3 GABA(A)R subtype-selective ligand (Rivas et al.), with significantly reduced ataxia/sedative effect, but with anticonvulsant, anxiolytic and anti-nociceptive properties. The ester moiety in Hz-166 was quickly metabolized in rodents to its corresponding carboxylic acid, which resulted to a suboptimal pharmacokinetics and precluded further study of it in rodents. A series of new heterocyclic bioisosteres at C-3 with various substituents were then designed, synthesized, and evaluated to improve brain penetrability and increase plasma and brain exposure. A novel lead compound, the 1,3-oxazole KRM-II-81 (Poe et al., J. Med. Chem., 2016) was the most promising candidate of the bioisostere series as a potent, αlpha1 sparing GABA(A)R ligand with excellent PK, and drug stability in rodent anxiety models. In addition, KRM-II-81 exhibited increased anticonvulsant potency and efficacy in rodent seizure-induction models. Moreover, it exhibited the anxiolytic-like effects in a Vogel conflict test and a mouse marble-burying assay compared to the parent Hz-166, with no sedative effects. Thus, KRM-II-81 represents a significant advance in the pharmacology of these anxiolytic and anticonvulsant imidazobenzodiazepines.

Synthesis of novel imidazobenzodiazepine oxazole bioisosteres as potential alpha 2, 3 subtype selective GABA(A) receptors agonists with excellent metabolic stability, pharmacokinetics, and anxiolytic efficacy

253rd National Meeting (2017)

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