Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation.

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2H)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved. Intratracheal administration of lead compound 26 resulted in a promising pharmacokinetic profile, thus demonstrating that the optimization strategy of in vitro profiles successfully translated to an in vivo setting.

Design, Synthesis, Structure-Activity Relationship Studies, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase.

We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB1. To understand the unexpected affinity for the CB1 receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.

Supramolecular Macrostructures of UPy-Functionalized Carbon Nanotubes.

Carbon nanotubes (CNTs) are considered excellent materials for the construction of flexible displays due to their nanoscale dimensions and unique physical and chemical properties. By using the recognition properties of 2-ureido-4[1H]pyrimidinone (UPy), a versatile and simple methodology was demonstrated for the construction of macroscopic structures based on UPy-CNT/polymer composites prepared by a combination of two functionalization approaches: 1) covalent attachment of UPy pendants on the multiwalled CNT surface (UPy-MWCNTs) and 2) directed self-assembly of UPy-MWCNTs within polymers bearing UPy pendants (Bis-UPy 1 and Bis-UPy 2) by quadruple complementary DDAA-AADD hydrogen-bond recognition (D=donor, A=acceptor).

Supramolecular assemblies of nucleoside functionalized carbon nanotubes: synthesis, film preparation, and properties.

Nucleoside-functionalized multi-walled carbon nanotubes (N-MWCNTs) were synthesized and characterized. A self-organization process using hydrogen bonding interactions was then used for the fabrication of self-assembled N-MWCNTs films free of stabilizing agents, polymers, or surfactants. Membranes were produced by using a simple water-dispersion-based vacuum-filtration method. Hydrogen-bond recognition was confirmed by analysis with IR spectroscopy and TEM images. Restoration of the electronic conduction properties in the N-MWCNTs membranes was performed by removing the organic portion by thermal treatment under an argon atmosphere to give d-N-MWCNTs. Electrical conductivity and thermal gravimetric analysis (TGA) measurements confirmed the efficiency of the annealing process. Finally, oxidative biodegradation of the films N-MWCNTs and d-N-MWCNTs was performed by using horseradish peroxidase (HRP) and low concentrations of H2 O2 . Our results confirm that functional groups play an important role in the biodegradation of CNT by HRP: N-MWCNTs films were completely biodegraded, whereas for d-N-MWCNTs films no degradation was observed, showing that the pristine CNT undergoes minimal enzyme-catalyzed oxidation This novel methodology offers a straightforward supramolecular strategy for the construction of conductive and biodegradable carbon nanotube films.

Synthesis of 1,2-dihydroxyindolizidines from 1-(2-pyridyl)-2-propen-1-ol.

1-(2-Pyridyl)-2-propen-1-ol, obtained by vinylation of commercially available picolinaldehyde, resulted a good starting material for the synthesis of the indolizidine skeleton. In particular, a simple process involving bromination, reduction, and nucleophilic substitution (via elimination and addition) allowed an easy conversion of the starting material into (±)-lentiginosine in ~27% overall yield.