Diaryl urea analogues of SB-334867 as orexin-1 receptor antagonists

Perrey, David A.; Gilmour, Brian P.; Runyon, Scott P.; Thomas, Brian F.; Zhang, Yanan

doi:10.1016/j.bmcl.2011.03.048

Cited by 18 publications

(28 citation statements)

References 29 publications

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“…25–27,33 In these assays, EC 50 curves of the agonist orexin-A were obtained alone and together with the test compound (15 minute pre-incubation), respectively, and the right-shift of the agonist curve was measured. The apparent dissociation constant K e was then calculated from compound-mediated inhibition of orexin A activity as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported our efforts in developing selective OX 1 antagonists, 25–27 in particular those based on the tetrahydroisoquinoline (THIQ) scaffold found in other orexin antagonists such as dual antagonist almorexant ( 1 ) and the OX 2 selective antagonist TCS-OX2-29 ( 2 ). We have synthesized and pharmacologically evaluated a series of 6,7-disubsituted THIQs and identified several highly potent and selective OX 1 antagonists such as RTIOX-276 ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

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The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

Perrey

Decker

et al. 2015

Bioorganic & Medicinal Chemistry

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Selective antagonism of the orexin 1 (OX1) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure-activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX1, indicating that the 7-position is important for OX1 antagonism (10c, Ke = 23.7 nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26a, Ke = 427 nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX1 receptor are competitive antagonists with slow dissociation rates.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

Perrey

Decker

et al. 2015

Bioorganic & Medicinal Chemistry

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“…In contrast, SB-408124 had no effect on sleep, physical activity, or body temperature after peripheral administration (240). Other selective orexin 1 receptor antagonists including SB-410220 (241) and diaryl urea analogues of SB-334867 (242) have been described pharmacologically; however, behavioral effects have yet to determined.…”

Section: Orexin and Neuromedin Receptors As Therapeutic Targetsmentioning

confidence: 99%

Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

Nixon

Kotz

Novak

et al. 2011

Handbook of Experimental Pharmacology

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In this section we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus–perifornical area, and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways, but is nonetheless a separate neural process that depends on interactions with other feeding related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite related neuromedin producing neurons are in hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the various other neuro-peptides, -transmitters, -modulators and –hormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.

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“…30, 31 It has a potency of ~40 nM at OX 1 and is at least 50-fold selective for OX 1 over OX 2 . Structure-activity relationship (SAR) studies have resulted in analogs with improved OX 1 selectivity, 32 but 1 remains an important tool to probe the pharmacology and function of OX 1 . Despite its wide application, 1 has limitations including a less than desirable pharmacokinetic profile and the recently discovered hydrolytic instability where the 2-methylbenzoxazole undergoes ring opening under acidic conditions.…”

Section: Introductionmentioning

confidence: 99%

Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor

et al. 2013

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Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats.

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Diaryl urea analogues of SB-334867 as orexin-1 receptor antagonists

Cited by 18 publications

References 29 publications

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor

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