Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 ().

1β-Hydroxydeoxycholic Acid as an Endogenous Biomarker in Human Plasma for Assessment of CYP3A Clinical Drug-Drug Interaction Potential.

4-Hydroxycholesterol (4-HC) in plasma has been used as a biomarker to assess CYP3A drug-drug interaction (DDI) potential during drug development. However, due to the long half-life and narrow dynamic range of 4-HC, its use has been limited to the identification of CYP3A inducers, but not CYP3A inhibitors. The formation of 1-hydroxydeoxycholic acid (1-OH DCA) from deoxycholic acid (DCA) is mediated by CYP3A, thus 1-OH DCA can potentially serve as an alternative to 4-HC for assessment of CYP3A DDI potential.

A Computational Physics-based Approach to Predict Unbound Brain-to-Plasma Partition Coefficient, K.

The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small-molecule central nervous system (CNS) drugs is characterized by a high unbound brain/plasma ratio (K). While various medicinal chemistry strategies and models have been reported to improve BBB penetration, they have limited application in predicting K directly.

Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists.

A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profiles compared to those of the original lead compound while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue demonstrated efficacy in a mouse oral glucose tolerance test and an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies.

Efficacy of Relebactam (MK-7655) in Combination with Imipenem-Cilastatin in Murine Infection Models.

The World Health Organization has identified antimicrobial resistance as a global public health threat since the prevalence and spread of antibiotic resistance among bacterial pathogens worldwide are staggering. Carbapenems, such as imipenem and meropenem, have been used to treat multidrug-resistant bacteria; however, since the development of resistance to carbapenems, β-lactam antibiotics in combination with β-lactamase inhibitors (BLI) has been one of the most successful strategies to enhance the activity of β-lactam antibiotics. Relebactam (REL) is a new BLI which has been found to inhibit class A and class C β-lactamases REL has been reported to restore imipenem's activity against both imipenem-resistant and Reported here are the efficacy studies of the imipenem-cilastatin (IMI)-REL combination in mouse models of disseminated and pulmonary infection caused by imipenem-resistant clinical isolates of and The combination was also evaluated in a delayed pulmonary model of infection.