TRV0109101, a G Protein-Biased Agonist of the -Opioid Receptor, Does Not Promote Opioid-Induced Mechanical Allodynia following Chronic Administration.

Prescription opioids are a mainstay in the treatment of acute moderate to severe pain. However, chronic use leads to a host of adverse consequences including tolerance and opioid-induced hyperalgesia (OIH), leading to more complex treatment regimens and diminished patient compliance. Patients with OIH paradoxically experience exaggerated nociceptive responses instead of pain reduction after chronic opioid usage.

Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers.

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.

Biased ligands at G-protein-coupled receptors: promise and progress.

Drug discovery targeting G protein-coupled receptors (GPCRs) is no longer limited to seeking agonists or antagonists to stimulate or block cellular responses associated with a particular receptor. GPCRs are now known to support a diversity of pharmacological profiles, a concept broadly referred to as functional selectivity. In particular, the concept of ligand bias, whereby a ligand stabilizes subsets of receptor conformations to engender novel pharmacological profiles, has recently gained increasing prominence.

First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers.

TRV130 is a G protein-biased ligand at the µ-opioid receptor. In preclinical studies it was potently analgesic while causing less respiratory depression and gastrointestinal dysfunction than morphine, suggesting unique benefits in acute pain management. A first-in-human study was conducted with ascending doses of TRV130 to explore its tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers.

First clinical experience with TRV027: pharmacokinetics and pharmacodynamics in healthy volunteers.

TRV027 is a novel β-arrestin biased peptide ligand of the angiotensin II type 1 receptor (AT1R). The compound antagonizes G protein coupling while simultaneously stimulating β-arrestin-mediated signaling. In preclinical studies, TRV027 reversibly reduced blood pressure while preserving renal function in a dog tachypaced heart failure model and stimulating cardiomyocyte contractility in vitro.

GPCR biased ligands as novel heart failure therapeutics.

G protein-coupled receptors have been successfully targeted by numerous therapeutics including drugs that have transformed the management of cardiovascular disease. However, many GPCRs, when activated or blocked by drugs, elicit both beneficial and adverse pharmacology. Recent work has demonstrated that in some cases, the salutary and deleterious signals linked to a specific GPCR can be selectively targeted by "biased ligands" that entrain subsets of a receptor's normal pharmacology.

A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine.

The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.

TRV120027, a novel β-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure.

Background: TRV120027 is a novel β-arrestin biased ligand of the angiotensin II type 1 receptor; it antagonizes canonical G-protein-mediated coupling while, in contrast to classical angiotensin II type 1 receptor antagonists, it engages β-arrestin-mediated signaling. Consequently, TRV120027 inhibits angiotensin II-mediated vasoconstriction while, via β-arrestin coupling, it increases cardiomyocyte contractility. We hypothesized that TRV120027 would elicit beneficial cardiorenal actions when added to furosemide in experimental heart failure.

Cardiorenal actions of TRV120027, a novel ß-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: a novel therapeutic strategy for acute heart failure.

Background: The angiotensin II type 1 receptor (AT1R) plays a key role in regulating cardiorenal function. Classic "unbiased" AT1R antagonists block receptor coupling to both G(αq) and ß-arrestin-mediated signals, which desensitize G-protein signaling as well as transduce G-protein-independent signals. TRV120027 is a novel ß-arrestin-biased AT1R ligand, which engages ß-arrestins while blocking G-protein signaling.

Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance.

Biased G protein-coupled receptor ligands engage subsets of the receptor signals normally stimulated by unbiased agonists. However, it is unclear whether ligand bias can elicit differentiated pharmacology in vivo. Here, we describe the discovery of a potent, selective β-arrestin biased ligand of the angiotensin II type 1 receptor.

Mechanical injury potentiates proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor alpha in immature bovine and adult human articular cartilage.

Objective: Traumatic joint injury can damage cartilage and release inflammatory cytokines from adjacent joint tissue. The present study was undertaken to study the combined effects of compression injury, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) and its soluble receptor (sIL-6R) on immature bovine and adult human knee and ankle cartilage, using an in vitro model, and to test the hypothesis that endogenous IL-6 plays a role in proteoglycan loss caused by a combination of injury and TNFalpha.

Methods: Injured or uninjured cartilage disks were incubated with or without TNFalpha and/or IL-6/sIL-6R.

Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.

The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.

Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury.

Objective: Acute joint injury leads to increased risk for osteoarthritis (OA). Although the mechanisms underlying this progression are unclear, early structural, metabolic, and compositional indicators of OA have been reproduced using in vitro models of cartilage injury. This study was undertaken to determine whether glycosaminoglycan (GAG) loss following in vitro cartilage injury is mediated by cellular biosynthesis, activation of enzymatic activity, or mechanical disruption of the cartilage extracellular matrix.

Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: interaction with exogenous cytokines.

Objective: Traumatic joint injury leads to an increased risk of osteoarthritis (OA), but the progression to OA is not well understood. We undertook this study to measure aspects of proteoglycan (PG) degradation after in vitro injurious mechanical compression, including up-regulation of enzymatic degradative expression and cytokine-stimulated degradation.

Methods: Articular cartilage tissue explants were obtained from newborn bovine femoropatellar groove and from adult normal human donor knee and ankle tissue.

Phenylbutyrates as potent, orally bioavailable vitronectin receptor (integrin alphavbeta3) antagonists.

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.

Rapid inhibition of thyroxine-induced bone resorption in the rat by an orally active vitronectin receptor antagonist.

An excess of thyroid hormone results in increased bone turnover and loss of bone mass in humans. Exogenous administration of thyroid hormone to rats has served as a model of human hyperthyroidism in which antiresorptive therapies have been tested. We have further refined this model of thyroxine (T4)-induced turnover in the rat.

Novel bone antiresorptive approaches.

Inhibition of bone resorption is a mechanism that has been clinically validated as a means to control bone loss in diseases such as postmenopausal osteoporosis. The development of marketable drugs in this area has resulted in significant clinical benefits; however, improvements can still be made. Several novel antiresorptive mechanisms are currently under consideration in the pharmaceutical industry, which will hopefully result in the development of improved bone antiresorptive therapies.

A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat.

Inhibition of the cyteine proteinase, cathepsin K (E.C. 3.