Development of a Scalable Process for DG-041, a Potent EP<sub>3</sub> Receptor Antagonist, via Tandem Heck Reactions

Zegar, Siead; Tokar, Christopher J.; Enache, Livia A.; Rajagopol, Venkat; Zeller, Wayne E.; O’Connell, Matthew J.; Singh, Jasbir; Muellner, Frank W.; Zembower, David E.

doi:10.1021/op700107h

Cited by 37 publications

(20 citation statements)

References 8 publications

(8 reference statements)

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“…1) revealed to be difficult. 92 7-Halo-3-indolecarbaldehyde (23) prepared by the BIS and Vilsmeier-Haack sequence is also the starting material for many biologically interesting products. For instance, it served as the key building block for the synthesis of a series of monohalide mercaptoacrylic acid derivatives, which were employed in a study View Article Online of SAR on the efficacy of these molecules for inhibition of Ca 2+ -activation of calpain-1 (Scheme 15).…”

Section: Syntheses From 7-haloindolesmentioning

confidence: 99%

Applications of Bartoli indole synthesis

2014

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In 1989, the reaction of vinyl magnesium halides with ortho-substituted nitroarenes leading to indoles was discovered. This reaction is now frequently reported as the "Bartoli reaction" or the "Bartoli indole synthesis" (BIS). It has rapidly become the shortest and most flexible route to 7-substituted indoles, because the classical indole syntheses generally fail in their preparation. The flexibility of the Bartoli reaction is great as it can be extended to heteroaromatic nitro derivatives and can be run on solid support. This review will focus on the use of the Bartoli indole synthesis as the key step in preparations of complex indoles, which appeared in the literature in the last few years.

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Section: Syntheses From 7-haloindolesmentioning

confidence: 99%

Applications of Bartoli indole synthesis

2014

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“…To evaluate the peripheral role of EP 3 receptors in bladder afferent functions, a peripherally limited EP 3 receptor antagonist, (2E)-3-{1-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl}-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041; see Ref. 44), was tested on the micturition reflex in a bladder rhythmic contraction model and on bladder pain sensation by measurement of visceromotor reflex (VMR) and cardiovascular (pressor) responses to noxious urinary bladder distension (UBD).…”

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confidence: 99%

An excitatory role for peripheral EP₃ receptors in bladder afferent function

Su¹,

Lashinger²,

Leon³

et al. 2008

American Journal of Physiology-Renal Physiology

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The excitatory roles of EP3 receptors at the peripheral afferent nerve innervating the rat urinary bladder have been evaluated by using the selective EP3 antagonist (2E)-3-{1-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl}-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041). The bladder rhythmic contraction model and a bladder pain model measuring the visceromotor reflex (VMR) to urinary bladder distension (UBD) have been used to evaluate DG-041 in female rats. In addition, male rats [spontaneously hypertensive rat (SHR), WistarKyoto (WKY), and Sprague-Dawley (SD)] were anesthetized with pentobarbital sodium, and primary afferent fibers in the L 6 dorsal root were isolated for recording the inhibitory response to UBD following intravenous injection of DG-041. Intravenous injection of DG-041 (10 mg/kg), a peripherally restricted EP 3 receptor antagonist, significantly reduced the frequency of bladder rhythmic contraction and inhibited the VMR response to bladder distension. The magnitude of reduction of the VMR response was not different in the different strains of rats (SD, SHR, and WKY). Furthermore, quantitative characterization of the mechanosensitive properties of bladder afferent nerves in SHR, WKY, and SD rats did not show the SHR to be supersensitive to bladder distension. DG-041 selectively attenuated responses of mechanosensitive afferent nerves to UBD, with strong suppression on the slow-conducting, high-threshold afferent fibers, with equivalent activity in the three strains. We conclude that sensitization of afferent nerve activity was not one of the mechanisms of bladder hypersensitivity in SHR. EP 3 receptors are involved in the regulation of bladder micturition and bladder nociception at the peripheral level.EP3; viscermotor reflex; bladder rhythmic contraction; bladder distension; afferent nerve SENSATION ASSOCIATED WITH the urinary bladder is conveyed primarily by pelvic and hypogastric nerves, by which the signal is relayed to the central nervous system (CNS). Most afferent fibers innervating the musculature of the bladder body pass through the pelvic nerve, whereas the majority of afferent endings in the bladder submucosa are derived from the hypogastric nerve (41), suggesting that the afferent fibers in the pelvic and hypogastric nerves have different roles, signaling mechanical stimulation (e.g., bladder distension) and chemical stimulation (e.g., inflammation), respectively (20,22,30,34). Bladder distension is a natural mechanical stimulus to evoke sensations such as fullness, urgency, and pain while the literature suggests a complex regulatory role of prostaglandins (PGs) in multiple aspects of urinary bladder physiology/pathophysiology. PGE 2 , one of the principal PGs, is synthesized in urothelium and detrusor smooth muscle (19,24,25,27) as well as in neurons and glial cells (18,23) and is released in response to various physiological (e.g., bladder distension) and pathological (e.g., mediators of inflammation) stimulation. PGE 2 interacts with four EP receptor subt...

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“…A selection of these reactions is shown in Table 4 [31][32][33][34][35][36][37][38]. A selection of these reactions is shown in Table 4 [31][32][33][34][35][36][37][38].…”

Section: Scheme 2 Gilmore Application Of the Bartoli Indole Synthesismentioning

confidence: 99%

Bartoli Indole Synthesis

Gribble

2016

Indole Ring Synthesis

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Development of a Scalable Process for DG-041, a Potent EP₃ Receptor Antagonist, via Tandem Heck Reactions

Cited by 37 publications

References 8 publications

Applications of Bartoli indole synthesis

Applications of Bartoli indole synthesis

An excitatory role for peripheral EP₃ receptors in bladder afferent function

Bartoli Indole Synthesis

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Development of a Scalable Process for DG-041, a Potent EP3 Receptor Antagonist, via Tandem Heck Reactions

Cited by 37 publications

References 8 publications

Applications of Bartoli indole synthesis

Applications of Bartoli indole synthesis

An excitatory role for peripheral EP3 receptors in bladder afferent function

Bartoli Indole Synthesis

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Development of a Scalable Process for DG-041, a Potent EP₃ Receptor Antagonist, via Tandem Heck Reactions

An excitatory role for peripheral EP₃ receptors in bladder afferent function