The first potent and selective inhibitors of the glycine transporter type 2.
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Amino Acid Transport Systems, Neutral↗
Biomedical subjects
J R Morphy
Publications and source records attributed to J R Morphy.
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.).
Amides↗
Synthesis of novel analogues of the delta opioid ligand SNC-80 using REM resin.
Focused libraries of delta opioid ligands were synthesised using REM resin methodology. Several high affinity compounds were identified with good selectivity over the mu opioid receptor. Automated REM resin recycling was used to synthesise larger amounts of ligand for in vivo studies.
Benzamides↗
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.
Aluminum Chloride↗
Inhibition of bone resorption in vitro by selective inhibitors of gelatinase and collagenase.
Two low-molecular-mass inhibitors of matrix metalloproteinases (MMPs), CT1166, a concentration-dependent selective inhibitor of gelatinases A and B, and Ro 31-7467, a concentration-dependent selective inhibitor of collagenase, were examined for their effects on bone resorption and type-I collagenolysis. The test systems consisted of measuring (1) the release of [3H]proline from prelabelled mouse calvarial explants; (2) the release of 14C from prelabelled type-I collagen films by mouse calvarial osteoblasts; and (3) lacunar resorption by isolated rat osteoclasts cultured on ivory slices. In 24 h cultures, CT1166 and Ro 31-7467 inhibited both interleukin-1 alpha- (IL-1 alpha; 10(-10) M) and 1,25-dihydroxyvitamin D3 (10(-8) M)-stimulated bone resorption in cultured neonatal mouse calvariae at concentration selective for the inhibition of gelatinase (10(-9) M for CT1166) and collagenase (10(-8) M for Ro 31-7467) respectively. For each compound the inhibition was dose-dependent, reversible, and complete at a 10(-7) M concentration. However, CT1166 (10(-9) M) and Ro 31-7467 (10(-8) M) in combination were required to completely abolish IL-1 alpha-stimulated bone resorption in mouse calvariae throughout a 96 h culture period. Neither of the inhibitors affected protein synthesis, DNA synthesis nor the IL-1 alpha-stimulated secretion of the lysosomal enzyme, beta-glucuronidase. Both CT1166 and Ro 31-7467 partially inhibited IL-1 alpha-stimulated lacunar resorption by isolated osteoclasts, but were without effect on unstimulated lacunar resorption. Rodent osteoclasts produced collagenase and gelatinases-A and -B activity. In contrast the substrate used to assess osteoclast lacunar resorption contained no detectable collagenase or gelatinase activity. Both compounds dose-dependently inhibited 1,25-dihydroxyvitamin D3 (10(-8) M)-stimulated degradation of type-I collagen by mouse calvarial osteoblasts; however, complete inhibition of collagenolysis was only achieved at concentrations at which CT1166 and Ro 31-7467 act as general MMP inhibitors. This study demonstrates that collagenase and gelatinases A and/or B participate in bone resorption. While these MMPs may be primarily involved in osteoid removal, we conclude that they may also be released by osteoclasts, where they participate in bone collagen degradation within the resorption lacunae.
Amides↗
Solid phase synthesis of tertiary amines on amide REM resins: Grignard and metal hydride compatible resins.
Four new amide REM resins (AM REM 2-5) are described, and their use is illustrated for the synthesis of tertiary amines 6-9 and 13-16. Amide REM resins 4 and 5, which have a phenyl ring attached to the amide nitrogen, are found to give superior product yields and purities, and the resins are stable to a wider range of reagents and conditions compared to REM resin 1.
Amides↗
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.
Animals↗
Solid-phase synthesis of cyclic imides.
A cyclative cleavage strategy for the synthesis of cyclic imides on a polystyrene resin is described. After optimization of the cleavage conditions, a small array of succinimides and phthalimides was synthesized. The methodology was then applied to a drug discovery project, in which it was used to synthesize a new class of delta-opioid receptor ligand by both automated and manual methods.
Combinatorial Chemistry Techniques↗