title: Discovery of a novel series of selective HCN1 blockers.
abstract: The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States. kmcclure@its.jnj.com
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: McClure
authors.forename: Michael
authors.initials: M
authors.lastname: Maher
authors.forename: Nancy
authors.initials: N
authors.lastname: Wu
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.forename: William A
authors.initials: WA
authors.lastname: Eckert
authors.forename: Dong H
authors.initials: DH
authors.lastname: Lee
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: Michelle
authors.initials: M
authors.lastname: Hermann
authors.forename: Brett
authors.initials: B
authors.lastname: Allison
authors.forename: Natalie
authors.initials: N
authors.lastname: Hawryluk
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Grice
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D015221:Potassium Channels / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578665:HCN1 protein, human; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007189:Indans; D015221:Potassium Channels