ABSTRACT
A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.
Subject(s)
Azetidines/chemical synthesis , Azetidines/pharmacology , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacology , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Female , Lipids/chemistry , Mice , Mice, Inbred C57BL , Models, Molecular , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Structure-Activity RelationshipABSTRACT
Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABA(B) receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABA(B) receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABA(B) receptor antagonist and absent in GABA(B)-/- mice). AZD3355 and baclofen differed markedly in their distribution in rat brain; AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABA(B) receptors and may offer a potential new approach to treatment of GERD.
Subject(s)
Esophageal Sphincter, Lower/drug effects , GABA Agonists/pharmacology , GABA-B Receptor Agonists , Peripheral Nerves/drug effects , Phosphinic Acids/pharmacology , Propylamines/pharmacology , Animals , Autoradiography , Baclofen/pharmacology , Binding, Competitive/drug effects , Calcium/metabolism , Dogs , Dose-Response Relationship, Drug , Esophageal Sphincter, Lower/innervation , Female , Ferrets/metabolism , GABA Plasma Membrane Transport Proteins/metabolism , Humans , Hypothermia/chemically induced , In Vitro Techniques , Membrane Potentials/drug effects , Mice , Muscle Relaxation/drug effects , Protein Binding , Protein Isoforms/metabolism , Rats , Rats, Sprague-Dawley , Receptors, GABA-B/metabolism , Vagus Nerve/drug effects , Vagus Nerve/physiologyABSTRACT
We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.
Subject(s)
GABA Agonists/chemistry , GABA Agonists/pharmacology , GABA-B Receptor Agonists , Gastroesophageal Reflux/drug therapy , Animals , Dose-Response Relationship, Drug , GABA Agonists/therapeutic use , Humans , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
The 13C NMR signals from the aromatic ring carbons in a series of lignin model compounds of the arylglycerol beta-aryl ether type in DMSO solution have been assigned. The model compounds investigated are representative of the erythro and threo forms of differently substituted arylglycerol beta-aryl ethers.
