Discovery of novel N-acylsulfonamide analogs as potent and selective EP3 receptor antagonists

Asada, Masaki; Obitsu, Tetsuo; Kinoshita, Atsushi; Nakai, Y.; Nagase, Toshihiko; Sugimoto, Isamu; Tanaka, Motoyuki; Takizawa, Hiroya; Yoshikawa, Kiwamu; Sato, Kazutoyo; Narita, Masami; Ohuchida, Shuichi; Nakai, Hisao; Toda, Masaaki

doi:10.1016/j.bmcl.2010.02.034

Cited by 23 publications

(18 citation statements)

References 19 publications

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“…[12] The use of N-acylbenzotriazoles as acylating agents was described by Katritzky et al: Primary and secondary sulfonamides were acylated in the presence of sodium hydride in 76%-100% yields. [14][15][16] This synthetic route generally works well, affording desired acylated products in satisfactory yields. [14][15][16] This synthetic route generally works well, affording desired acylated products in satisfactory yields.…”

Section: Acylation Of Sulfonamidesmentioning

confidence: 99%

“…[48,49] SAR studies were performed on acylsulfonamide EP 3 antagonists: A number of new compounds were discovered, with improved potency and selectivity toward other prostanoid receptors. [15] The receptor subtype EP 4 is involved in many physiological processes, as anti-inflammatory, tissue development and regeneration, and regulation of vascular tone and hemostasis. [15] The receptor subtype EP 4 is involved in many physiological processes, as anti-inflammatory, tissue development and regeneration, and regulation of vascular tone and hemostasis.…”

Section: Ep 3 -Ep 4 Receptor Antagonists (Prostanoid Receptor Antagmentioning

confidence: 99%

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N‐acylsulfonamides: Synthetic routes and biological potential in medicinal chemistry

et al. 2017

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Sulfonamide is a common structural motif in naturally occurring and synthetic medicinal compounds. The rising interest in sulfonamides and N-acyl derivatives is attested by the large number of drugs and lead compounds identified in last years, explored in different fields of medicinal chemistry and showing biological activity. Many acylsulfonamide derivatives were designed and synthesized as isosteres of carboxylic acids, being the characteristics of these functional groups very close. Starting from chemical routes to N-acylsulfonamides, this review explores compounds of pharmaceutical interest, developed as enzymatic inhibitors or targeting receptors.

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Section: Acylation Of Sulfonamidesmentioning

confidence: 99%

Section: Ep 3 -Ep 4 Receptor Antagonists (Prostanoid Receptor Antagmentioning

confidence: 99%

N‐acylsulfonamides: Synthetic routes and biological potential in medicinal chemistry

et al. 2017

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“…Ethylenesulfonamide substituents (–CH 2 CH 2 SO 2 NRR′) linked directly to arenes are very common structural elements in medicinal chemistry. They are often synthesized by Pd‐catalysed hydrogenation of a styrylsulfonyl derivative . One example is sulfonamide 14 , which was tested as a potential inhibitor of the prostaglandin‐E 2 receptor EP‐3 .…”

Section: Introductionmentioning

confidence: 99%

“…They are often synthesized by Pd‐catalysed hydrogenation of a styrylsulfonyl derivative . One example is sulfonamide 14 , which was tested as a potential inhibitor of the prostaglandin‐E 2 receptor EP‐3 . Epoxide 15 was obtained from the underlying styrylsulfonamide by epoxidation with KOCl; it was tested successfully for the treatment of filarial infections in an animal model .…”

Section: Introductionmentioning

confidence: 99%

Styrylsulfonates and ‐Sulfonamides through Pd‐Catalysed Matsuda–Heck Reactions of Vinylsulfonic Acid Derivatives and Arenediazonium Salts

2016

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Arene diazonium salts undergo Matsuda-Heck reactions with vinylsulfonates and -sulfonamides to give styrylsulfonic acid derivatives in high to excellent yields and with high to excellent selectivities. By quantifying the evolution of nitrogen over time in a gas-meter apparatus, the reactivities of ethylvinylsulfonate and the benchmark olefin methyl acrylate were compared for an electron-rich and an -deficient arene diazonium salt. Tertiary sulfonamides react in Matsuda-Heck couplings with high conversions, but require long reaction

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“…N -acylsulfonamides are common carboxylic acid bioisosteres that have been successfully implemented in antagonists of angiotensin II AT1 receptors 26 as well as EP3 receptors. 27 A series of analogs ( 8 - 21 ) resulting from the amidation of 7 was prepared (Table 3). Tertiary amide analogues of 7 ( 9 and 14 ) were included to evaluate a structure-activity role of an acidic proton in ligand-receptor interactions.…”

mentioning

confidence: 99%

Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere

Downey

Saleh

Bridges

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Recent preclinical studies demonstrate a role for the prostaglandin E2 (PGE2) subtype 1 (EP1) receptor in mediating, at least in part, the pathophysiology of hypertension and diabetes mellitus. A series of amide and N-acylsulfonamide analogs of a previously described picolinic acid-based human EP1 receptor antagonist (7) were prepared. Each analog had improved selectivity at the mouse EP1 receptor over the mouse thromboxane receptor (TP). A subset of analogs gained affinity for the mouse PGE2 subtype 3 (EP3) receptor, another potential therapeutic target. One analog (17) possessed equal selectivity for EP1 and EP3, displayed a sufficient in vivo residence time in mice, and lacked the potential for acyl glucuronide formation common to compound 7. Treatment of mice with 17 significantly attenuated the vasopressor activity resulting from an acute infusion of EP1 and EP3 receptor agonists. Compound 17 represents a potentially novel therapeutic in the treatment of hypertension and diabetes mellitus.

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Discovery of novel N-acylsulfonamide analogs as potent and selective EP3 receptor antagonists

Cited by 23 publications

References 19 publications

N‐acylsulfonamides: Synthetic routes and biological potential in medicinal chemistry

N‐acylsulfonamides: Synthetic routes and biological potential in medicinal chemistry

Styrylsulfonates and ‐Sulfonamides through Pd‐Catalysed Matsuda–Heck Reactions of Vinylsulfonic Acid Derivatives and Arenediazonium Salts

Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere

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