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Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.

The first example of one-pot sequential Cope/Rauhut-Currier reactions are reported and used to make functionalized decalin structures with all-carbon quaternary stereocenters. The substrates for the new sequential reaction are generated through a six-step sequence including an enantioselective Birch reduction-allylation reaction which makes the overall process asymmetric.

Examining rates of deicing salt accumulation and leaching in urban soils is important for understanding the distribution and movement of salt in the environment. We examined autumn concentrations of deicing salts in soils in a moderately dense urban landscape in eastern New York State. The study area contrasted to the isolated, rural highways examined in previous studies. While NaCl was the most abundantly applied salt, Mg2+ (apparently from MgCl2, a secondary deicing salt) was the most abundant salt cation in soils. Moderate Na+ levels, and equivalent concentrations at depth and in surface samples, indicate that leaching of Na+ is rapid in this system. Leaching may ameliorate toxicity for land plants but accelerate inputs to aquatic systems. In contrast to rural highway studies, where salt levels declined rapidly with distance to pavement, Na+ remained elevated at the maximum distance measured. Airborne salt dispersal and dense networks of pavement likely contribute to widespread elevated salt levels. This semi-urban setting had salt levels high enough to be toxic to terrestrial plants and soil protozoa. Even moderate levels of development can have dramatic effects on salt inputs into soils and aquatic systems.

The enantioselective synthesis of highly functionalized decalin structures is achieved through one-pot sequential Cope/Rauhut—Currier reaction of substrates (I).

The 3-chloro-4-carboxamido-6-arylpyridazines are a novel class of interleukin-1β converting enzyme (ICE) inhibitor. These agents are irreversible inhibitors with pyridazine 23 possessing a k obs [I] = 355 M−1s−1. A structure-activity relationship for this non-peptide class of compounds and the putative mechanism for irreversible inactivation are described.

Restoration of p53 activity by inhibition of the p53–MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein–protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53–MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.

A series of non-peptide competitive antagonists of the human IMR 90 fetal lung fibroblast bradykinin B2 receptor have been designed and synthesized. Compound 15 binds with an affinity constant Ki = 60 nM. The SAR leading to the design of these non-peptide antagonists is described.

Structural and stereochemical requirements of substrate based time-dependent inactivators of interleukin-1β converting enzyme were investigated. Hydrophobic amino acids with L-stereochemistry are preferred at the P 2 and P 3 positions. It appears that both D-and L-Asp are accepted by the enzyme at the P I position.

[13223-25-1] C6H7ClN2O2 (MW 174.0196) InChI = 1S/C6H7ClN2O2/c1-10-4-3-5(11-2)9-6(7)8-4/h3H,1-2H3 InChIKey = PBEKEFWBLFBSGQ-UHFFFAOYSA-N (reagent used in nucleophilic substitution, carbonylation, nitration, Pechmann condensation reaction, Tisler triazolopyrimidine cyclization, cross-coupling) Physical Data: colorless crystals, mp 100–105 °C.1 Solubility: insol H2O; sol methyl alcohol, diethyl ether, chloroform, toluene, N,N-dimethylformamide, acetonitrile. Form Supplied in: colorless crystals, widely available. Purification: recrystallization, isopropyl alcohol and water. Handling, Storage, and Precautions: toxic by inhalation, in contact with skin, and if swallowed.

[7688-51-9] C9H23NSi2 (MW 201.4562) InChI = 1S/C9H23NSi2/c1-8-9-10(11(2,3)4)12(5,6)7/h8H,1,9H2,2-7H3 InChIKey = CVNCFZIIZGNVFD-UHFFFAOYSA-N (reagent used as an electrophile, nucleophilic component, and to functionalize ω-primary amine polystyrenes) Alternate Names: N-allyl-N,N-bis(trimethylsilyl)amine, 1,1,1-trimethyl-N-2-propene-1-yl-N-(trimethylsilyl)-silanamine, allyl hexamethyldisilazane (AHMDS). Physical Data: bp 72 °C/15 mmHg; d 0.816 g cm−3 at 25 °C. Solubility: insol H2O; sol methyl alcohol, diethyl ether, dichloromethane. Form Supplied in: colorless liquid; widely available. Purification: distilled under reduced pressure (15 mmHg). Handling, Storage, and Precautions: is an irritant and should be used only in a well-ventilated fume hood with proper personal equipment (wear suitable gloves, protective clothing, and eye/face protection).

A series of non-peptide competitive antagonists of the human IMR 90 fetal lung fibroblast bradykinin B2 receptor have been designed and synthesized. Compound 15 binds with an affinity constant Ki = 60 nM. The SAR leading to the design of these non-peptide antagonists is described.

A concise synthesis of the β-amyloid 1–42 aggregation inhibitor (−)-5,8-dihydroxy-3 R -methyl-2 R -(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(−)- 2 ] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene 6 into amine 9 . Enantiomeric resolution was achieved by recrystallization of amine 9 as the dibenzoyl- d -tartaric acid salt. Hydroquinone 2 is a potent inhibitor of the fibrillar aggregation of β-amyloid as determined in two different assay systems.

The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the galanin 1 receptor (GAL-R1). Using an HTS assay based on 125I-human galanin binding to the human galanin-1 receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affinity IC50's to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin analogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in secondary assays involving adenylate cyclase activity and GTP binding to G-proteins. Analogues 7 and 23 were also active in functional assays involving galanin, reversing the inhibitory effect of galanin on acetylcholine (ACh) release in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch.