title: Synthesis and evaluation of diphenylphosphinic amides and diphenylphosphine oxides as inhibitors of Kv1.5.
abstract: Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 μM were discovered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included.
authors.affiliation: Respiratory & Inflammation iMed, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden. Roine.i.olsson@astrazeneca.com
authors.forename: Roine I
authors.initials: RI
authors.lastname: Olsson
authors.forename: Ingemar
authors.initials: I
authors.lastname: Jacobson
authors.forename: Jonas
authors.initials: J
authors.lastname: Boström
authors.forename: Tomas
authors.initials: T
authors.lastname: Fex
authors.forename: Annika
authors.initials: A
authors.lastname: Björe
authors.forename: Christina
authors.initials: C
authors.lastname: Olsson
authors.forename: Johan
authors.initials: J
authors.lastname: Sundell
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gran
authors.forename: Anna
authors.initials: A
authors.lastname: Öhrn
authors.forename: Andreas
authors.initials: A
authors.lastname: Nordin
authors.forename: Jonna
authors.initials: J
authors.lastname: Gyll
authors.forename: Maria
authors.initials: M
authors.lastname: Thorstensson
authors.forename: Ahlke
authors.initials: A
authors.lastname: Hayen
authors.forename: Karolina
authors.initials: K
authors.lastname: Aplander
authors.forename: Olle
authors.initials: O
authors.lastname: Hidestål
authors.forename: Fanyi
authors.initials: F
authors.lastname: Jiang
authors.forename: Gunilla
authors.initials: G
authors.lastname: Linhardt
authors.forename: Elin
authors.initials: E
authors.lastname: Forsström
authors.forename: Teresa
authors.initials: T
authors.lastname: Collins
authors.forename: Monika
authors.initials: M
authors.lastname: Sundqvist
authors.forename: Emma
authors.initials: E
authors.lastname: Lindhardt
authors.forename: Annika
authors.initials: A
authors.lastname: Åstrand
authors.forename: Boel
authors.initials: B
authors.lastname: Löfberg
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010087:Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010720:Phosphines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D051666:Kv1.5 Potassium Channel; D010087:Oxides; D010720:Phosphines; D010721:Phosphinic Acids; C507236:(2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide; C010574:biphenyl