Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain.

Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.

Human and environmental controls over aboveground carbon storage in Madagascar.

BACKGROUND: Accurate, high-resolution mapping of aboveground carbon density (ACD, Mg C ha-1) could provide insight into human and environmental controls over ecosystem state and functioning, and could support conservation and climate policy development. However, mapping ACD has proven challenging, particularly in spatially complex regions harboring a mosaic of land use activities, or in remote montane areas that are difficult to access and poorly understood ecologically. Using a combination of field measurements, airborne Light Detection and Ranging (LiDAR) and satellite data, we present the first large-scale, high-resolution estimates of aboveground carbon stocks in Madagascar. RESULTS: We found that elevation and the fraction of photosynthetic vegetation (PV) cover, analyzed throughout forests of widely varying structure and condition, account for 27-67% of the spatial variation in ACD. This finding facilitated spatial extrapolation of LiDAR-based carbon estimates to a total of 2,372,680 ha using satellite data. Remote, humid sub-montane forests harbored the highest carbon densities, while ACD was suppressed in dry spiny forests and in montane humid ecosystems, as well as in most lowland areas with heightened human activity. Independent of human activity, aboveground carbon stocks were subject to strong physiographic controls expressed through variation in tropical forest canopy structure measured using airborne LiDAR. CONCLUSIONS: High-resolution mapping of carbon stocks is possible in remote regions, with or without human activity, and thus carbon monitoring can be brought to highly endangered Malagasy forests as a climate-change mitigation and biological conservation strategy.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Pharmacokinetic optimisation of novel indole-2-carboxamide cannabinoid CB1 antagonists.

The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.

Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists.

Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.

The discovery of novel indole-2-carboxamides as cannabinoid CB(1) receptor antagonists.

The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.

Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor.

Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.

High-resolution forest carbon stocks and emissions in the Amazon.

Efforts to mitigate climate change through the Reduced Emissions from Deforestation and Degradation (REDD) depend on mapping and monitoring of tropical forest carbon stocks and emissions over large geographic areas. With a new integrated use of satellite imaging, airborne light detection and ranging, and field plots, we mapped aboveground carbon stocks and emissions at 0.1-ha resolution over 4.3 million ha of the Peruvian Amazon, an area twice that of all forests in Costa Rica, to reveal the determinants of forest carbon density and to demonstrate the feasibility of mapping carbon emissions for REDD. We discovered previously unknown variation in carbon storage at multiple scales based on geologic substrate and forest type. From 1999 to 2009, emissions from land use totaled 1.1% of the standing carbon throughout the region. Forest degradation, such as from selective logging, increased regional carbon emissions by 47% over deforestation alone, and secondary regrowth provided an 18% offset against total gross emissions. Very high-resolution monitoring reduces uncertainty in carbon emissions for REDD programs while uncovering fundamental environmental controls on forest carbon storage and their interactions with land-use change.

Rapid access towards follow-up NOP receptor agonists using a knowledge based approach.

A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.

Structure-activity relationships and CoMFA of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic properties.

The N-3 position of a series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues was optimised using the predictive power of a CoMFA model. The model was used to prioritise compounds for synthesis culminating in the triazole (+)-24. (+)-24 was found to be a high affinity, potent NOP agonist and demonstrated both antinociceptive and antiallodynic effects when administered iv to rodents.

Synthesis and evaluation of N-3 substituted phenoxypropyl piperidine benzimidazol-2-one analogues as NOP receptor agonists with analgesic and sedative properties.

A series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues have been discovered as novel NOP receptor agonists. Structure-activity relationships have been explored via N-3 substitution of the benzimidazol-2-one with a range of functionality. The N-methyl acetamide derivative (+)-7f was found to be a high-affinity, potent NOP agonist with greater than 100-fold selectivity over the MOP receptor. Furthermore (+)-7f was shown to be both antinociceptive and sedative when administered iv to rodents.

Synthesis and SAR studies of 3-phenoxypropyl piperidine analogues as ORL1 (NOP) receptor agonists.

A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified.

Quaternary salts of E2020 analogues as acetylcholinesterase inhibitors for the reversal of neuromuscular block.

A series benzylpiperidinium and benzylpyridinium quaternary salts have been synthesised and tested for inhibition of acetylcholinesterase and reversal of neuromuscular block induced by vecuronium. Several potent reversal agents have been identified and their haemodynamic effects measured.

Novel piperidinium and pyridinium agents as water-soluble acetylcholinesterase inhibitors for the reversal of neuromuscular blockade.

A series of piperidinium and pyridinium agents containing a common structural fragment of 5,6-dimethoxybenzothiophene have been synthesised as water-soluble acetylcholinesterase inhibitors. Several compounds, for example 42 (AChE IC(50) 0.03 microM) have been found to reverse the neuromuscular blockade induced by vecuronium bromide in vitro and in vivo. Coupled with their high water solubility (up to 30-60 mg/mL), these compounds are potentially useful as intravenous reversal agents of neuromuscular blocking agents in surgical anaesthesia.

Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships.

A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.

New approaches to reversal of neuromuscular block.

Although numerous reversal agents for neuromuscular block (NMB) have been known for some time, investigations on new approaches were initiated only recently. The different approaches used in an attempt to avoid the muscarinic side effects associated with the antagonists of NMB that are currently available are reviewed.