Novel Benzamide-Based Histamine H3 Receptor Antagonists: The Identification of Two Candidates for Clinical Development

Abstract

ABSTRACT:The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H 3 receptor antagonists is described. The compounds described are high affinity histamine H 3 antagonists. Optimization of the physical properties of these histamine H 3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.

UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H3 and H4 Receptors

“…hyperalgesia, Alzheimer's disease 187 , schizophrenia 188 or multiple sclerosis 184 . 169 Additionally, Johnson & Johnson (JNJ) completed several clinical studies for Attention Deficit Hyperactivity Disorder (ADHD) with the benzamide JNJ-31001074 189 (Figure 1.3). 169 With the results of a trial with e.g.…”

Design, synthesis, biological evaluation, and molecular docking of novel flavones as H3R inhibitors

“…H 3 R not only modulates the synthesis and release of histamine from histaminergic neurons, but also has a modulatory effect on other neurotransmitters including acetylcholine (ACh), norepinephrine (NE), dopamine (DA), serotonin (5‐HT), and others. H 3 R is associated with neurobehaviors such as cognition, the sleep–wake cycle, and anxiety . Furthermore, inhibition of H 3 R enhances memory performance and improves cognitive ability .…”

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates**

“…Antidepressant piberaline ( 38 ) was prepared from picolinic acid ( 39 ) via stepwise mechanochemical amide coupling, [41] solvent‐free Boc‐deprotection, [60] and mechanochemical amination steps. Derivatives of 4‐(hydroxymethyl)benzoic acid ( 42 ) have multiple pharmaceutical uses, including anticancer agents (e. g., Imanitib, [61] Masitinib [62] ), histone deacetylase inhibitors, [63] histamine receptor antagonists (e. g., Bavisant) [64] . The observed low reactivity of TCFH reagent towards alcohols compared to TFFH (see Scheme 2C) and, conversely, the high amide coupling potency of the TCFH/K 2 HPO 4 reagent system [41] was utilized to perform protecting group‐free mechanochemical amidation of carboxylic group in 42 (Scheme 6) while leaving the benzylic hydroxy group intact.…”