Search

Ketamine is a rapid-onset antidepressant whose efficacy long outlasts its pharmacokinetics. Multiple studies suggest ketamine's antidepressant effects require increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-dependent currents, which have recently been exclusively attributed to its N -methyl- d -aspartate receptor-inactive metabolite (2 R ,6 R)-hydroxynorketamine ((2 R ,6 R)-HNK). To investigate this AMPAR-activation claim further, we estimated and evaluated preclinically and clinically relevant unbound brain HNK concentrations (C b,u). (2 S ,6 S)-HNK and (2 R ,6 R)-HNK were novelly synthesized, and their neuropharmacokinetic profiles were determined to project relevant C b,u. Using concentrations (0.01–10 μM) bracketing the pertinent cross-species C b,u , both compounds' AMPAR modulation was assessed in vitro by electrophysiological recordings and GluA1 surface expression. Neither (2 S ,6 S)-HNK nor (2 R ,6 R)-HNK bound orthosterically to or directly functionally activated AMPARs. (2 R ,6 R)-HNK failed to evoke AMPAR-centric changes in any electrophysiological endpoint from adult rodent hippocampal slices. Conversely, time- and concentration-dependent increases in GluA1 expression occurred only with (2 R ,6 R)-HNK (≥0.1 μM at ≥90 min). The (2 R ,6 R)-HNK concentrations that increased GluA1 expression are consistent with its maximal C b,u (0.92–4.84 μM) at reportedly efficacious doses of ketamine or (2 R ,6 R)-HNK in mouse depression models, but ≥3-fold above its projected maximal human C b,u (≤37.8 ± 14.3 nM) following ketamine's clinically antidepressant infusion. These findings provide insight into the observed AMPAR-affecting (2 R ,6 R)-HNK concentrations versus its exposures attained clinically at an antidepressant ketamine dose. To optimize any clinical study with (2 R ,6 R)-HNK to fully assess its translational pharmacology, future preclinical work should test (2 R ,6 R)-HNK concentrations and/or C b,u of 0.01–0.1 μM to parallel its projected human C b,u at a clinically antidepressant ketamine dose. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is characterized by accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles in the brain. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aβ fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling. Further evaluation in an LC-MS/MS “cold tracer” study in rodents revealed high specific binding to BACE1 in brain. Upon radiolabeling, [18F]3 demonstrated favorable brain uptake and high in vivo specificity in nonhuman primate (NHP), suggesting its potential for imaging BACE1 in humans. [ABSTRACT FROM AUTHOR]

A major challenge in the development of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development. [ABSTRACT FROM AUTHOR]

Theidentification of centrally efficacious β-secretase (BACE1)inhibitors for the treatment of Alzheimer’s disease (AD) hashistorically been thwarted by an inability to maintain alignment ofpotency, brain availability, and desired absorption, distribution,metabolism, and excretion (ADME) properties. In this paper, we describea series of truncated, fused thioamidines that are efficiently selectivein garnering BACE1 activity without simultaneously inhibiting theclosely related cathepsin D or negatively impacting brain penetrationand ADME alignment, as exemplified by 36. Upon oral administration,these inhibitors exhibit robust brain availability and are efficaciousin lowering central Amyloid β (Aβ) levels in mouse anddog. In addition, chronic treatment in aged PS1/APP mice effects adecrease in the number and size of Aβ-derived plaques. Mostimportantly, evaluation of 36in a 2-week exploratorytoxicology study revealed no accumulation of autofluorescent materialin retinal pigment epithelium or histology findings in the eye, issuesobserved with earlier BACE1 inhibitors. [ABSTRACT FROM AUTHOR]

The aspartyl protease β-secretase, or BACE, hasbeen demonstrated to be a key factor in the proteolytic formationof Aβ-peptide, a major component of plaques in the brains ofAlzheimer’s disease (AD) patients, and inhibition of this enzymehas emerged as a major strategy for pharmacologic intervention inAD. An X-ray-based fragment screen of Pfizer’s proprietaryfragment collection has resulted in the identification of a novelBACE binder featuring spiropyrrolidine framework. Although exhibitingonly weak inhibitory activity against the BACE enzyme, the small compoundwas verified by biophysical and NMR-based methods as a bona fide BACEinhibitor. Subsequent optimization of the lead compound, relying heavilyon structure-based drug design and computational prediction of physiochemicalproperties, resulted in a nearly 1000-fold improvement in potencywhile maintaining ligand efficiency and properties predictive of goodpermeability and low P-gp liability. [ABSTRACT FROM AUTHOR]

Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with the bicyclo[1.1.1]-pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (∼4-fold ↑ Cmax and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]-pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness. [ABSTRACT FROM AUTHOR]

Abstract: The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure–activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold. [Copyright &y& Elsevier]

Structure–activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted. [Copyright &y& Elsevier]

3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The aromatic derivatives of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-positive and Gram-negative bacteria. [Copyright &y& Elsevier]