Discovery and development of a novel N-(3-bromophenyl)-{[(phenylcarbamoyl)amino]methyl}-N-hydroxythiophene-2-carboximidamide indoleamine 2,3-dioxygenase inhibitor using knowledge-based drug design.

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.

Lower body negative pressure-induced vagal reaction: role for the osmopressor response?

BACKGROUND: Water ingestion elicits an osmopressor response in patients with impaired baroreflexes. In young, healthy subjects, water elicits sympathetic vasoconstriction. This study investigated the effect of water on the lower body negative pressure (LBNP)-induced vasovagal reaction and also analyzed its effect on the change of regional cerebral blood flow during LBNP. METHODS: Twelve young healthy subjects underwent LBNP (40 mm Hg) tolerance testing for 45 minutes or until presyncopal symptoms occurred. Subjects received either LBNP or no LBNP with or without prior water ingestion. The severity of vasovagal reaction was determined by participant self-report rating of orthostatic symptoms during the LBNP test. Changes of regional cerebral blood flow (rCBF) between LBNP and water ingestion with LBNP groups were assessed using statistical parametrical mapping analyses. RESULTS: Water ingestion attenuated the severity of symptomatic scores during LBNP (P = 0.004). Water ingestion increased Total peripheral vascular resistance (P < 0.001) and attenuated the blood pressure drop (P < 0.001) at the cessation of study. LBNP decreased rCBF over the left superior prefrontal gyrus, limbic-parahippocampal gyrus, left sublobar-caudate body, and hypothalamus (P < 0.001). Water increased rCBF significantly over the right frontal lobe, including the inferior and medial prefrontal gyrus, subcallosal, and sublobar insula, during LBNP stimulation (P < 0.001). CONCLUSIONS: Water ingestion strongly reduces symptomatic burden of the vasovagal reaction induced by LBNP stimulation. The cortical activation of limbic and prefrontal cortex likely indicates the involvement of osmopressor response in central autonomic cardiovascular physiology. The central cortical activation of osmopressor response might provide insight into the mechanisms by which water ingestion reduces the vasovagal reaction.