Dedicated to the memory of Prof. Walter A. SzarekIndoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC 50 = 0.16 μM, EC 50 = 0.3 μM). Structuralactivity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.

IntroductionAnxiogenic and anxiolytic effects of cannabinoids are mediated by different mechanisms, including neural signaling via cannabinoid receptors (CBRs) and nicotinic cholinergic receptors (nAChRs). This study examined the effects of prior nicotine (the psychoactive component in tobacco) exposure on behavioral sensitivity to delta‐9‐tetrahydrocannabinol (THC; the psychoactive component of cannabis) challenge in animals.MethodsMale and female adult Sprague‐Dawley rats (N = 96) were injected daily with nicotine (1 mg/kg, i.p.) or vehicle for 14 days, followed by a 14‐day drug‐free period. On test day, rats were injected with THC (0.5, 2.0, or 5.0 mg/kg, i.p.) or vehicle and anxiety‐related behavior was assessed in the emergence (EM), elevated plus maze (EPM), and social interaction (SI) tests.ResultsChronic nicotine pretreatment attenuated some of the anxiogenic effects induced by THC challenge which can be summarized as follows: (a) THC dose‐dependently affected locomotor activity, exploratory behavior, and social interaction in the EM, EPM, and SI tests of unconditioned anxiety; (b) these effects of acute THC challenge were greater in females compared with males except for grooming a conspecific; (c) prior nicotine exposure attenuated the effects of acute THC challenge for locomotor activity in the EPM test; and (d) prior nicotine exposure attenuated the effects of THC challenge for direct but not indirect physical interaction in the SI tests.ConclusionsThe ability of nicotine prior exposure to produce long‐lasting changes that alter the effects of acute THC administration suggests that chronic nicotine may induce neuroplastic changes that influence the subsequent response to novel THC exposure.

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The Front Cover illustrates the ‘molecule to mind’ structural hierarchy of pathology and symptoms arising from Alzheimer's disease. Although Alzheimer's presents as a disorder of thought, memory, and cognition, it is a disease that we seek to treat not at the cellular level, but at the molecular level. Given that the brain is the most complex structure in the universe, and that Alzheimer's is the most complex disease of brain, the search for new treatments must address all possible avenues. The brain's immune system is an important emerging druggable target; we describe our identification of indoleamine 2,3‐dixoygenase inhibitors as putative disease modifying therapies for Alzheimer's. More information can be found in the Communication by Donald F. Weaver et al.