Design and synthesis of a maximally diverse and druglike screening library using REM resin methodology.

A 3042 compound screening library was synthesized using a combination of two solid-phase technologies: REM resin methodology and Lewis acid promoted aminolysis. The exclusivity and structural diversity of the library were enhanced by using a highly divergent synthetic strategy involving 13 different scaffolds (9 of which were custom-made), five different types of resin-bound phenol derivatization chemistry (Mitsunobu, Suzuki, acylation, sulfonylation, and carbamoylation), and three different cleavage strategies (Hofmann elimination, AlCl(3)-promoted aminolysis, base-promoted esterolysis). This is the first example of a solid-phase Suzuki coupling involving a resin-bound aryl triflate being used for library synthesis. Computational analysis suggested that the compounds are likely to have favorable properties for CNS penetration. Analysis of the library by HPLC and MS suggested at least 90% of the sampled members were present in an average purity of approximately 70%. Encouragingly, hits have been identified from high-throughput screening of this library, such as compound 6, which has an affinity of 1.02 microM for the GlyT(2) transporter.

Parallel synthesis and biological activity of a new class of high affinity and selective delta-opioid ligand.

A considerable number of research papers describing the synthesis and testing of the delta opioid receptor (DOR) ligands, SNC-80 and TAN-67, and analogues of these two compounds, have been published in recent years. However, there have been few reports of the discovery of completely new structural classes of selective DOR ligand. By optimising a hit compound identified by high throughput screening, a new series of tetrahydroisoquinoline sulphonamide-based delta opioid ligands was discovered. The main challenge in this series was to simultaneously improve both affinity and physicochemical properties, notably aqueous solubility. The most active ligand had an affinity (IC(50)) of 6 nM for the cloned human DOR, representing a 15-fold improvement relative to the original hit 1 (IC(50) 98 nM). Compounds from this new series show good selectivity for the DOR over mu and kappa opioid receptors. However the most active and selective compounds had poor aqueous solubility. Improved aqueous solubility was obtained by replacing the phthalimide group in 1 by basic groups, allowing the synthesis of salt forms. A series of compounds with improved affinity and solubility relative to 1 was identified and these compounds showed activity in an in vivo model of antinociception, the formalin paw test. In the case of compound 19, this analgesic activity was shown to be mediated primarily via a DOR mechanism. The most active compound in vivo, 46, showed superior potency in this test compared to the reference DOR ligand, TAN-67 and similar potency to morphine (68% and 58% inhibition in Phases 1 and 2, respectively, at a dose of 10 mmol/kg i.v.).

Non-depolarizing neuromuscular blocking activity of bisquaternary amino di- and tripeptide derivatives.

Herein we describe the synthesis of novel di- and tripeptide derivatives with two quaternary nitrogen groups attached and the biological testing of these compounds for neuromuscular blocking (NMB) activity in vitro and in vivo. The short peptide scaffold was selected because it offers potential for desired distance between the two pharmacophoric quaternary nitrogen groups, short duration of action, straightforward synthesis, and compatibility with an injectable formulation. From a small series of compounds 20c,e are identified as effective non-depolarizing NMB agents in vitro and in vivo in anesthetized cats and Rhesus monkeys with potencies similar to those of the clinical reference compounds rocuronium (4) and suxamethonium (2) (monkey ED(90) = 0.68, 0.23, 0.16, 5.04 micromol/kg, respectively). These new peptide derivatives 20c,e have similar potency and onset time but longer duration and slower recovery than the clinically used reference compounds. The structure-activity relationships described for this chemical series lead to the conclusion that the di- or tripeptide fragment can be regarded as an alternative template to the steroid or aliphatic ester of previously reported NMBs and within this tripeptide-derived series clog P correlates well with in vitro NMB activity.

Synthesis of novel analogues of the delta opioid ligand SNC-80 using AlCl3-promoted aminolysis.

Two focused libraries of delta opioid ligands were synthesised using AlCl3 facilitated aminolysis. Several compounds were identified with DOR binding affinities higher or similar to SNC-80. A novel acyclic derivative of SNC-80 produced antinociception in the acetic acid abdominal constriction test, which is at least partially mediated via the delta-opioid receptor.

Donor leg morbidity after pedicled rectus femoris muscle flap transfer for abdominal wall and pelvic reconstruction.

The pedicled rectus femoris muscle and myocutaneous flap has found application for a variety of soft tissue defects of the groin, pelvis, and lower abdomen. Although a number of authors have discussed the usefulness of this muscle flap, few have documented the morbidity from loss of this muscle in the leg. We have studied 7 patients who underwent unilateral rectus femoris muscle transfer, comparing strength of the donor knee to the normal knee. All patients were studied using a computerized dynamometer for strength of knee flexion and contraction. We found that loss of the rectus femoris in patients not undergoing a postoperative program of therapy led to an average decrease in strength about the knee of 24% to 28%, depending on the motion measured. A single patient who underwent an intensive postoperative therapy program had return of normal strength in his donor leg. Despite this common loss of strength, patient complaints were few and the results of reconstruction appeared to outweigh this loss of strength.