The evolution of histamine H₃ antagonists/inverse agonists.
This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.
Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Evan P
EP
Lebois
Carrie K
CK
Jones
Craig W
CW
Lindsley
D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism; D055808:Drug Discovery; D054314:Drug Inverse Agonism; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D018100:Receptors, Histamine H3 / Q000378:metabolism; D013329:Structure-Activity Relationship
D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3