Discovery of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.

Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder.

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

Post-procedure surveillance in liver biopsy: how long is long enough?

AIM: To assess the incidence of complications following liver biopsy and the impact of pre-procedural pethidine on complications and analgesia administration. METHOD: A retrospective audit of percutaneous liver biopsies undertaken at Dunedin Public Hospital (2001-2006). Patients' medical files were consulted for demographics, biopsy indication, complications, frequency, and timing of analgesia. RESULTS: 447 biopsies were analysed. Primary indications included: hepatitis C (38.8%), abnormal liver function tests (18.3%), methotrexate therapy (12.5%), and malignancy (10.3%). 303 (68%) biopsies resulted in no complications. Major complications were not experienced. Minor complications included: pain (32.2%), hypotension (1.3%), nausea/vomiting (0.9%), and alcohol withdrawal (0.2%). More females (47%) than males (31%) reported complications. Post-procedural analgesia was administered in 31% of biopsies; only 9% required analgesia more than 2 hours after biopsy. Patients who had pre-procedural pethidine experienced similar rates of complications as patients not receiving pre-procedural pethidine, but received less post-procedural opiate analgesia. CONCLUSION: No major complications occurred, whilst the rate of minor complications was comparable with previous studies. Pain was the most common complication, although use of analgesia after 2 hours of observation was low. Our findings suggest that post-procedural observation may safely be reduced to two hours but it is currently unknown if early mobilisation following discharge will lead to complications.

Tetrahydroisoquinoline derivatives as melatonin MT2 receptor antagonists.

A series of tetrahydroisoquinolines has yielded potent MT(2) receptor antagonists, which are selective versus the MT(1) receptor.

Chronobiotic activity of N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]-propanamide. Synthesis and melatonergic pharmacology of fluoren-9-ylethyl amides.

A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.