The Discovery of Phthalazinone-Based Human H₁and H₃Single-Ligand Antagonists Suitable for Intranasal Administration for the Treatment of Allergic Rhinitis

Abstract

A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.

The Efficacy and Tolerability of Two Novel H₁/H₃ Receptor Antagonists in Seasonal Allergic Rhinitis

“…One molecule was designed for oral administration (GSK835726) and the other for intranasal administration (GSK1004723), as it is unclear which route of administration has the greatest potential to maximise relief of nasal congestion. The doses chosen in our studies were expected to be active at both the H 1 and H 3 receptors based on preclinical pharmacology data [22,24,25]. …”

“…Two novel H 1 /H 3 dual antagonists have been developed that both display H 1 as well as H 3 antagonist activity [22]. It was proposed that these novel H 1 /H 3 antagonists, known as GSK1004723 and GSK835726, would offer a breakthrough in allergic rhinitis, since they would not only provide relief from the symptoms which are attenuated by H 1 receptor blockade such as rhinorrhoea, sneezing and itching, but would also provide relief from nasal congestion through H 3 receptor antagonism resulting in enhanced sympathetically mediated nasal vascular constriction [20,21].…”

Pd‐Catalyzed Cross‐Coupling with Organometals Containing Zn, Al, Zr, and so on – The Negishi Coupling and Its Recent Advances

“…Many of the recently reported potential drug candidates [224][225][226][227] and natural products were synthesized by using a Negishi cross-coupling as one of the key steps in the total synthesis. Some of the representative structures of biologically active compounds are shown in Table 3.15.…”

Several down, a few to go: histamine H3receptor ligands making the final push towards the market?

“…The SAR and biological profile for GSK-1004723 (23) (pK i hH 1 R = 8.0 and pK i hH 3 R = 9.6) have been extensively described [141]. The phthalazinone part of the H 1 R antagonist Azelastine (21) (i.e., scaffold 22) was taken as a starting point for developing the H 1 R/H 3 R dual ligands.…”