Using electrophysiology and in silico three-dimensional modeling to reduce human Ether-à-go-go related gene K(+) channel inhibition in a histamine H3 receptor antagonist program.
The histamine H3 receptor (H3R) plays a regulatory role in the presynaptic release of histamine and several other neurotransmitters, and thus, it is an attractive target for central nervous system indications including cognitive disorders, narcolepsy, attention-deficit hyperactivity disorder, and pain. The development of H3R antagonists was complicated by the similarities between the pharmacophores of H3R and human Ether-à-go-go related gene (hERG) channel blockers, a fact that probably prevented promising compounds from being progressed into the clinic. Using a three-dimensional in silico modeling approach complemented with automated and manual patch clamping, we were able to separate these two pharmacophores and to develop highly potent H3R antagonists with reduced risk of hERG liabilities from initial hit series with low selectivity identified in a high-throughput screening campaign.
Evotec Ltd., Milton Park, Abingdon, United Kingdom.
Adam J
AJ
Davenport
Clemens
C
Möller
Alexander
A
Heifetz
Michael P
MP
Mazanetz
Richard J
RJ
Law
Andreas
A
Ebneth
Mark J
MJ
Gemkow
D000818:Animals; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D054828:Histamine H3 Antagonists / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D051638:Ether-A-Go-Go Potassium Channels; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3