Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1.

A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 µmol/kg compared to control.

Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors.

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ∼500µM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4µM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization.

Radiochemical synthesis and in vivo evaluation of [18F]AZ11637326: an agonist probe for the α7 nicotinic acetylcholine receptor.

INTRODUCTION: The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET). METHODS: We prepared the high-affinity (K(d) = 0.2 nM) α7 nAChR agonist, 5'-(2-[(18)F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [(18)F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [(18)F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates. RESULTS: [(18)F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90 min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/µmol (3,781 mCi/µmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. CONCLUSION: Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET.

Identification of N-(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides as novel inhibitors of GlyT1.

A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC(50) 37 nM, solubility 14 microM), the most potent GlyT1 inhibitor in this series. Favorable brain-plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration.

Synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, an analogue of 15R-lipoxin A4.

We describe a method for the synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, a compound that has been described as a metabolically stable analogue of 15R-lipoxin A(4).