Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs)

Arikawa, Yasuyoshi; Hasuoka, Atsushi; Nishida, Haruyuki; Hirase, Keizo; Inatomi, Nobuhiro; Takagi, Terufumi; Tarui, Naoki; Kawamoto, Masuki; Imanishi, Akihito; Itoh, Fumio; Kajino, Masahiro

doi:10.1016/j.bmcl.2015.03.094

Cited by 5 publications

(1 citation statement)

References 15 publications

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“…S1B). The rapid and long-lasting acid suppression by P-CABs is expected to provide more immediate and efficient therapy for acid-related disease 5 . SCH28080 contains a imidazo[1,2- a ]pyridine framework shared by a large subclass of P-CABs that competitively inhibit binding of the stimulating counterion, K + (Fig.…”

Section: Introductionmentioning

confidence: 99%

The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors

Abe¹,

Shimokawa²,

Naito³

et al. 2017

Sci Rep

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The gastric proton pump H+,K+-ATPase acidifies the gastric lumen, and thus its inhibitors, including the imidazo[1,2-a]pyridine class of K+-competitive acid blockers (P-CABs), have potential application as acid-suppressing drugs. We determined the electron crystallographic structure of H+,K+-ATPase at 6.5 Å resolution in the E2P state with bound BYK99, a potent P-CAB with a restricted ring structure. The BYK99 bound structure has an almost identical profile to that of a previously determined structure with bound SCH28080, the original P-CAB prototype, but is significantly different from the previously reported P-CAB-free form, illustrating a common conformational change is required for P-CAB binding. The shared conformational changes include a distinct movement of transmembrane helix 2 (M2), from its position in the previously reported P-CAB-free form, to a location proximal to the P-CAB binding site in the present BYK99-bound structure. Site-specific mutagenesis within M2 revealed that D137 and N138, which face the P-CAB binding site in our model, significantly affect the inhibition constant (K i) of P-CABs. We also found that A335 is likely to be near the bridging nitrogen at the restricted ring structure of the BYK99 inhibitor. These provide clues to elucidate the binding site parameters and mechanism of P-CAB inhibition of gastric acid secretion.

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Section: Introductionmentioning

confidence: 99%

The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors

Abe¹,

Shimokawa²,

Naito³

et al. 2017

Sci Rep

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Catalyst‐Free Difunctionalization of Activated Alkenes in Water: Efficient Synthesis of β‐Keto Sulfides and Sulfones

Wang

et al. 2016

Chemistry A European J

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Difunctionalization of activated alkenes, a powerful strategy in chemical synthesis, has been accomplished for direct synthesis of a series of β-keto sulfides and β-keto sulfones. The transformation, mediated by O2 , proceeds smoothly in water and without any catalyst. Prominent advantages of this method include mild reaction conditions, purification simplicity, and gram-scale synthesis, underlining the practical utility of this methodology.

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Synthesis of Functionalized β-Keto Arylthioethers by the Aryne Induced [2,3] Stevens Rearrangement of Allylthioethers

et al. 2017

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A mild and transition-metal-free synthesis of β-keto arylthioethers has been developed by the aryne triggered [2,3] Stevens rearrangement of allylthioethers. The key sulfur ylide intermediate for the rearrangement was formed by the S-arylation of allylthioethers with arynes generated from 2-(trimethylsilyl)aryl triflates using CsF. Later, the reaction products are converted into valuable heterocycles in two steps.

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Synthetic studies of five-membered heteroaromatic derivatives as potassium-competitive acid blockers (P-CABs)

Cited by 5 publications

References 15 publications

The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors

The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors

Catalyst‐Free Difunctionalization of Activated Alkenes in Water: Efficient Synthesis of β‐Keto Sulfides and Sulfones

Synthesis of Functionalized β-Keto Arylthioethers by the Aryne Induced [2,3] Stevens Rearrangement of Allylthioethers

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