Blocking Alcoholic Steatosis in Mice with a Peripherally Restricted Purine Antagonist of the Type 1 Cannabinoid Receptor

Type 1 cannabinoid receptor (CB1) antagonists have demonstrated promise for the treatment of obesity, liver disease, metabolic syndrome, and dyslipidemias. However, the inhibition of CB1 receptors in the central nervous system can produce adverse effects, including depression, anxiety, and suicidal ideation. Efforts are now underway to produce peripherally restricted CB1 antagonists to circumvent CNS-associated undesirable effects. In this study, a series of analogues were explored in which the 4-aminopiperidine group of compound <b>2</b> was replaced with aryl- and heteroaryl-substituted piperazine groups both with and without a spacer. This resulted in mildly basic, potent antagonists of human CB1 (hCB1). The 2-chlorobenzyl piperazine, <b>25</b>, was found to be potent (<i>K</i>_i = 8 nM); to be >1000-fold selective for hCB1 over hCB2; to have no hERG liability; and to possess favorable ADME properties including high oral absorption and negligible CNS penetration. Compound <b>25</b> was tested in a mouse model of alcohol-induced liver steatosis and found to be efficacious. Taken together, <b>25</b> represents an exciting lead compound for further clinical development or refinement

Identification of 1‑({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)‑1<i>H</i>‑pyrazol-3-yl]carbonyl}amino)cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound

Compounds active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects on different types of nociceptive modalities, including thermal, mechanical, and chemical stimuli. The NTS2 preferring peptide JMV-431 (<b>2</b>) and the NTS2 selective nonpeptide compound levocabastine (<b>6</b>) have been shown to be effective in relieving the pain associated with peripheral neuropathies. With the aim of identifying novel nonpeptide compounds selective for NTS2, we examined analogues of SR48692 (<b>5a</b>) using a FLIPR calcium assay in CHO cells stably expressing rat NTS2. This led to the discovery of the NTS2 selective nonpeptide compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1<i>H</i>-pyrazol-3-yl]­carbonyl}­amino)­cyclohexane carboxylic acid (NTRC-739, <b>7b</b>) starting from the nonselective compound <b>5a</b>

Identification of 2‑({[1-(4-Fluorophenyl)-5-(2-meth­oxy­phen­yl)‑1<i>H</i>‑pyr­azol-3-yl]­carb­onyl}ami­no)tri­cyclo[3.3.1.13,7]­dec­ane-2-carb­oxy­lic Acid (NTRC-844) as a Selective Antagonist for the Rat Neurotensin Receptor Type 2

Neurotensin receptor type 2 (NTS2) compounds display analgesic activity in animal pain models. We have identified the first high-affinity NTS2-selective antagonist (<b>8</b>) that is active in vivo. This study also revealed that the NTS2 FLIPR assay designation for a compound, agonist, partial agonist, and so forth, did not correlate with its in vivo activity as observed in the thermal tail-flick acute model of pain. This suggests that calcium mobilization is not the signaling pathway involved in NTS2-mediated analgesia as assessed by the thermal tail-flick model. Finally, we found a significant bias between rat and human for compound <b>9</b> in the NTS2 binding assay

Multiple copies of a tumor epitope in a recombinant hepatitis B surface antigen (HBsAg)vaccine enhance CTL responses, but not tumor protection

We propose the replacement of endogenous epitopes with foreign epitopes to exploit the highly immunogenic hepatitis B surface antigen (HBsAg) as a vaccine vector to elicit disease-protective cytotoxic T-Iymphocyte (CTL) responses. Locations were defined within the HBsAg gene where replacements of DNA encoding HBsAg epitopes may be made to generate functional recombinant (r) HBsAg DNA vaccines. We demonstrate that rHBsAg DNA vaccines encoding multiple copies of a model tumor epitope from human papillornavirus (HPV) elicit enhanced CTL responses compared to rHBsAg DNA vaccines encoding a single copy. We show that rHBsAg DNA vaccines elicit a marked prophylactic and long-lived therapeutic protection against epitope expressing tumor, although protective efficacy was not improved by increasing the number of copies of the tumor epitope DNA. These results demonstrate the efficacy of HBsAg as a vector for the delivery of foreign CTL epitopes using the epitope replacement strategy, and have implications for rHBsAg vaccine design. The results also have implications for the derivation of a therapeutic vaccine for HPV-associated squamous carcinoma