Synthesis of Triazolodiazepinium Salts: Sequential [3++2] Cycloaddition/Rearrangement Reaction of 1-Aza-2-azoniaallenium Cation Intermediates Generated from Piperidin-4-ones.

The bicyclic 1-aza-2-azoniaallenium salt intermediates, generated from the azoester species upon treatment with a Lewis acid, have been demonstrated to participate in Huisgen-type cycloaddition with nitriles to result in the formation of fused 6,7,8,9-tetrahydro-5 H-[1,2,4]triazolo[1,5- d][1,4]diazepinium salts. This transformation is interpreted as a regular [3++2] cycloaddition between intermediates as the reactive 1,3-monopole reactants and nitriles as the nucleophilic reagents followed by spontaneous [1,2]-cationic rearrangement. The azoester precursors were easily accessible via oxidation of the corresponding hydrazones using hypervalent iodine oxidant PhI(OAc)2 under mild conditions. The [1,2,4]triazolodiazepine compounds represent a class of N-containing biologically important heterocycles with a new type of scaffold.

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3+ + 2]-cycloaddition/rearrangement reactions.

Two new series of tricyclic heterocycles, namely 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepinium salts 10 and the related neutral, free bases 13 were synthesized from 4-acetoxy-1-acetyl-4-phenylazo-1,2,3,4-tetrahydroquinolines 8 and nitriles 9 in the presence of aluminium chloride by the [3+ + 2]-cycloaddition reaction of the in situ generated azocarbenium intermediates 14 followed by a ring-expansion rearrangement. In the rearrangement reaction, the phenyl substituent in the initially formed spiro-triazolium adducts 16 underwent a [1,2]-migration from C(3) to the electron-deficient N(2). This led to the ring expansion from 6-membered piperidine to 7-membered diazepine furnishing the tricyclic 1,2,4-triazole-fused 1,4-benzodiazepines.

Discovery of thiadiazole amides as potent, S1P3-sparing agonists of sphingosine-1-phosphate 1 (S1P1) receptor.

High-throughput screening of GSK compound collection led to the discovery of a novel series of thiadiazole amides as potent and S1P(3)-sparing sphingosine-1-phosphate 1 (S1P(1)) receptor agonists. Synthesis, structure and activity relationship, selectivity, and some developability properties are described.

Indole-propionic acid derivatives as potent, S1P3-sparing and EAE efficacious sphingosine-1-phosphate 1 (S1P1) receptor agonists.

Novel indole-propionic acid derivatives were developed as sphingosine-1-phosphate (S1P) receptor agonists through a systematic SAR study. The optimized and S1P(3) selective S1P(1) agonist 9f induced peripheral blood lymphocyte reduction in vivo and has an excellent efficacy in mouse experimental autoimmune encephalomyelitis (EAE).

Discovery of CNS Penetrant CXCR2 Antagonists for the Potential Treatment of CNS Demyelinating Disorders.

Structure-activity relationship exploration of the historical biarylurea series led to the identification of novel CNS penetrant CXCR2 antagonists with nanomolar potency, favorable PK profile, and good developability potentials. More importantly, the key compound 22 showed efficacy in a cuprizone-induced demyelination model with twice daily oral administration, thereby supporting CXCR2 to be a potential therapeutic target for the treatment of demyelinating diseases such as multiple sclerosis.

Study of the molecularly imprinted polymers for selective binding of the mono-substituted sulfonylurea herbicides.

A new molecularly imprinted polymer (MIP) was synthesized for the selective extraction of mono-substituted sulfonylurea herbicides, with monosulfuron as the template and acrylamide as the functional monomer. The recognition property and affinity of the MIP for monosulfuron and its analog, monosulfuron-ester, were evaluated by equilibrium adsorption and a chromatographic study. Computer modeling, including simulated annealing and semi-empirical quantum calculation, was employed to study the recognition mechanism. The computer modeling demonstrated that monosulfuron can form multiple hydrogen bonds with methacrylic acid and acrylamide, whereas monosulfuron-ester cannot form a stable complex with these two functional monomers, which aligns with the results of the rebinding experiment. The selectivity study further demonstrated that binding sites in the MIP interact with the hydrogen in the acylamino group of mono-substituted sulfonylurea. A comparison experiment also showed that monosulfuron-imprinted MIP offers better selectivity for monosulfuron-ester than the commercial C18 high-performance liquid chromatography stationary phase material.

Discovery of novel 1,2,4-thiadiazole derivatives as potent, orally active agonists of sphingosine 1-phosphate receptor subtype 1 (S1P(1)).

A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P(1) agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (F(u) > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS.