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Literature DB >> 28697302

Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators.

Joshua M Wieting¹, Anish K Vadukoot², Swagat Sharma², Kristopher K Abney³, Thomas M Bridges¹, J Scott Daniels⁴, Ryan D Morrison⁴, Kevin Wickman⁵, C David Weaver^6,7, Corey R Hopkins².

Abstract

The G protein-gated inwardly-rectifying potassium channels (GIRK, Kir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent Kp > 0.6).

Entities: CellLine Chemical Disease Gene Mutation Species

Keywords: GIRK; Kir3; activator; pharmacokinetics; thallium flux

Mesh：

Substances：

Year: 2017 PMID： 28697302 PMCID： PMC6116837 DOI： 10.1021/acschemneuro.7b00217

Source DB: PubMed Journal: ACS Chem Neurosci ISSN： 1948-7193 Impact factor: 4.418

18 in total

1. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes.

Authors: R S Obach
Journal: Drug Metab Dispos Date: 1999-11 Impact factor: 3.922

Review 2. G protein-activated inwardly rectifying potassium channels as potential therapeutic targets.

Authors: Toru Kobayashi; Kazutaka Ikeda
Journal: Curr Pharm Des Date: 2006 Impact factor: 3.116

Review 3. The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery.

Authors: Nicola F Smith; Florence I Raynaud; Paul Workman
Journal: Mol Cancer Ther Date: 2007-02 Impact factor: 6.261

Review 4. Inwardly rectifying potassium channels: their structure, function, and physiological roles.

Authors: Hiroshi Hibino; Atsushi Inanobe; Kazuharu Furutani; Shingo Murakami; Ian Findlay; Yoshihisa Kurachi
Journal: Physiol Rev Date: 2010-01 Impact factor: 37.312

5. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery.

Authors: J Cory Kalvass; Tristan S Maurer
Journal: Biopharm Drug Dispos Date: 2002-11 Impact factor: 1.627

6. Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.

Authors: Wandong Wen; Wenjun Wu; Ian M Romaine; Kristian Kaufmann; Yu Du; Gary A Sulikowski; C David Weaver; Craig W Lindsley
Journal: Bioorg Med Chem Lett Date: 2013-06-20 Impact factor: 2.823

7. G-protein-gated inwardly rectifying K+ channel 4 (GIRK4) immunoreactivity in chemically defined neurons of the hypothalamic arcuate nucleus that control body weight.

Authors: Vaia Kloukina; Silke Herzer; Niklas Karlsson; Monica Perez; Teresa Daraio; Björn Meister
Journal: J Chem Neuroanat Date: 2012-03-23 Impact factor: 3.052

8. Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297.

Authors: Nicole Wydeven; Ezequiel Marron Fernandez de Velasco; Yu Du; Michael A Benneyworth; Matthew C Hearing; Rachel A Fischer; Mark John Thomas; C David Weaver; Kevin Wickman
Journal: Proc Natl Acad Sci U S A Date: 2014-07-07 Impact factor: 11.205

Review 9. New insights into the therapeutic potential of Girk channels.

Authors: Rafael Luján; Ezequiel Marron Fernandez de Velasco; Carolina Aguado; Kevin Wickman
Journal: Trends Neurosci Date: 2013-11-21 Impact factor: 13.837

10. Use of a novel rapid and resource-efficient cassette dosing approach to determine the pharmacokinetics and CNS distribution of small molecule 7-transmembrane receptor allosteric modulators in rat.

Authors: Thomas M Bridges; Ryan D Morrison; Frank W Byers; Shuanghui Luo; J Scott Daniels
Journal: Pharmacol Res Perspect Date: 2014-09-01

9 in total

1. VU0810464, a non-urea G protein-gated inwardly rectifying K⁺ (K_ir 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K_ir 3 channels and reduces stress-induced hyperthermia in mice.

Authors: Baovi N Vo; Kristopher K Abney; Allison Anderson; Ezequiel Marron Fernandez de Velasco; Michael A Benneyworth; John Scott Daniels; Ryan D Morrison; Corey R Hopkins; Charles David Weaver; Kevin Wickman
Journal: Br J Pharmacol Date: 2019-05-30 Impact factor: 8.739

2. Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators.

Authors: Swagat Sharma; Krystian A Kozek; Kristopher K Abney; Sushil Kumar; Nagsen Gautam; Yazen Alnouti; C David Weaver; Corey R Hopkins
Journal: Bioorg Med Chem Lett Date: 2019-01-23 Impact factor: 2.823

3. Discovery, synthesis and biological characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators.

Authors: Swagat Sharma; Lauren Lesiak; Christopher D Aretz; Yu Du; Sushil Kumar; Nagsen Gautam; Yazen Alnouti; Nikilesh V Dhuria; Yashpal S Chhonker; C David Weaver; Corey R Hopkins
Journal: RSC Med Chem Date: 2021-06-21

Review 4. Neuronal G protein-gated K⁺ channels.

Authors: Haichang Luo; Ezequiel Marron Fernandez de Velasco; Kevin Wickman
Journal: Am J Physiol Cell Physiol Date: 2022-06-15 Impact factor: 5.282

5. The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents.

Authors: Yu Xu; Lucas Cantwell; Andrei I Molosh; Leigh D Plant; Dimitris Gazgalis; Stephanie D Fitz; Erik T Dustrude; Yuchen Yang; Takeharu Kawano; Sumanta Garai; Sami F Noujaim; Anantha Shekhar; Diomedes E Logothetis; Ganesh A Thakur
Journal: J Biol Chem Date: 2020-01-17 Impact factor: 5.157

Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators.

1. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes.

Review 2. G protein-activated inwardly rectifying potassium channels as potential therapeutic targets.

Review 3. The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery.

Review 4. Inwardly rectifying potassium channels: their structure, function, and physiological roles.

5. Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery.

6. Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.

7. G-protein-gated inwardly rectifying K+ channel 4 (GIRK4) immunoreactivity in chemically defined neurons of the hypothalamic arcuate nucleus that control body weight.

8. Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297.

Review 9. New insights into the therapeutic potential of Girk channels.

10. Use of a novel rapid and resource-efficient cassette dosing approach to determine the pharmacokinetics and CNS distribution of small molecule 7-transmembrane receptor allosteric modulators in rat.

1. VU0810464, a non-urea G protein-gated inwardly rectifying K⁺ (K_ir 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal K_ir 3 channels and reduces stress-induced hyperthermia in mice.

2. Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators.

3. Discovery, synthesis and biological characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators.

Review 4. Neuronal G protein-gated K⁺ channels.

5. The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents.

Review 6. Advances in Targeting GIRK Channels in Disease.

Review 7. Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.

8. A novel small-molecule selective activator of homomeric GIRK4 channels.

Review 9. Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry.

Review 2. G protein-activated inwardly rectifying potassium channels as potential therapeutic targets.

Review 3. The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery.

Review 4. Inwardly rectifying potassium channels: their structure, function, and physiological roles.

Review 9. New insights into the therapeutic potential of Girk channels.

Review 4. Neuronal G protein-gated K+ channels.

Review 6. Advances in Targeting GIRK Channels in Disease.

Review 7. Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.

Review 9. Pyrazolyl-Ureas as Interesting Scaffold in Medicinal Chemistry.

Review 4. Neuronal G protein-gated K⁺ channels.