As part of a therapeutic approach to idiopathic pulmonary fibrosis (IPF) using inhaled ALK5 inhibitors, which enable targeted lung delivery while minimizing systemic side effects, this work describes the optimization process of a previously reported series featuring a 4,6-disubstituted pyridazine core. The medicinal chemistry exploration, aimed at increasing cellular potency while keeping physicochemical and ADME properties favorable for inhalation, was directed to the functionalization of the 3-position in the pyridazine core. An efficient SAR exploration, supported by a late-stage functionalization (LSF) approach, led to the identification of a small set of compounds worthy of in vivo characterization. Compound 20 showed a persistent and lung-restricted target engagement in a pharmacodynamic model, which well-correlated with its in vitro solubility measured in simulated lung fluid (SLF). When tested in a mouse model of lung fibrosis, 20 showed remarkable efficacy, thus representing an advanced lead candidate for the development of topical antifibrotic therapeutics.

ALK5 inhibitors represent an attractive therapeutic approach for the treatment of a variety of pathologies, including cancer and fibrosis. Herein, we report the design and in vitro characterization of a novel series of ALK5 modulators featuring a 4,6-disubstituted pyridazine core. A knowledge-based scaffold-hopping exploration was initially conducted on a restricted set of heteroaromatic cores using available ligand- and structure-based information. The most potent structurally novel hit compound 2A was subsequently subjected to a preliminary optimization for the inhaled delivery, applying physicochemical criteria aimed at minimizing systemic exposure to limit the risk of adverse side effects. The resulting inhibitors showed a marked boost in potency against ALK5 and in vitro ADME properties, potentially favoring lung retention. The optimized hits 20 and 23 might thus be considered promising starting points for the development of novel inhaled ALK5 inhibitors.

In CNS, the 5-hydroxytryptamine1A (5-HT1A) receptors exist in two different populations with different behavioural and physiological effects: (1) somatodendritic autoreceptors located pre-synaptically of 5-HT containing neurons and (2) receptors located post-synaptic to 5-HT containing neurons. Clinical studies have shown that 5-HT1A partial agonists have anxiolytic properties, while antagonists of pre-synaptical autoreceptors shorten the onset time of selective serotonin reuptake inhibitors (SSRIs). In the present study, the pre- and post-synaptic activity of structural analogues of buspirone was evaluated in animal models. A three dimensional model of the 5-HT1A receptor was used to study their interaction modes and helical displacements upon receptor binding. The predicted receptor–ligand interactions indicated similarities in the receptor binding modes for all buspirone analogues, and no clear relationship between receptor contact residues and activity at pre- and post-synaptic receptors. Comparative molecular dynamics (MD) simulations for 650 ps indicated that pre-synaptic antagonistic behaviour is connected to large displacements of transmembrane helix (TMH) 7 upon binding, while pre-synaptic agonistic behaviour is connected to large displacements of TMH2 and small displacements of TMH7. Post-synaptic partial agonist behaviour is connected to large displacements of TMH4 and TMH5 upon binding, while post-synaptic antagonists only slightly displace these helices.

BACKGROUND AND PURPOSE Despite growing evidence that inhibition of α6β2‐containing (α6β2*) nicotinic acetylcholine receptors (nAChRs) may be beneficial for the therapy of tobacco addiction, the lack of good sources of α6β2*‐nAChRs has delayed the discovery of α6β2‐selective antagonists. Our aim was to generate a cell line stably expressing functional nAChRs with α6β2 properties, to enable pharmacological characterization and the identification of novel α6β2‐selective antagonists. EXPERIMENTAL APPROACH Different combinations of the α6, β2, β3, chimeric α6/3 and mutant β3 V273S subunits were transfected in human embryonic kidney cells and tested for activity in a fluorescent imaging plate reader assay. The pharmacology of rat immune‐immobilized α6β2*‐nAChRs was determined with 125 I‐epibatidine binding. KEY RESULTS Functional channels were detected after co‐transfection of α6/3, β2 and β3 V273S subunits, while all other subunit combinations failed to produce agonist‐induced responses. Stably expressed α6/3β2β3 V273S ‐nAChR pharmacology was unique, and clearly distinct from α4β2‐, α3β4‐, α7‐ and α1β1δε‐nAChRs. Antagonist potencies in inhibiting α6/3β2β3 V273S ‐nAChRs was similar to their binding affinity for rat native α6β2*‐nAChRs. Agonist affinities for α6β2*‐nAChRs was higher than their potency in activating α6/3β2β3 V273S ‐nAChRs, but their relative activities were equivalent. Focussed set screening at α6/3β2β3 V273S ‐nAChRs, followed by cross‐screening with the other nAChRs, led to the identification of novel α6β2‐selective antagonists. CONCLUSIONS AND IMPLICATIONS We generated a mammalian cell line stably expressing nAChRs, with pharmacological properties similar to native α6β2*‐nAChRs, and used it to identify novel non‐peptide, low molecular weight, α6β2‐selective antagonists. We also propose a pharmacophore model of α6β2 antagonists, which offers a starting point for the development of new smoking cessation agents.

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT1 autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.

L'invention concerne des composes representes par la formule (I) et leurs procedes de preparation, des intermediaires utilises dans ces procedes, des compositions pharmaceutiques contenant les derives et leur utilisation en therapie en tant qu'inhibiteurs du recaptage de la serotonine (5-HT), de la dopamine (DA) et de la norepinephrine (NE).

A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.

A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.

Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.

The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.

Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT1A/B/D receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT1A/B/D receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.

8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT(1A/B/D) receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.