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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.

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.

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.

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.