Brian Thomas O'neill

Discovery of 4-(5-Methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a Novel α7 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders in Schizophrenia: Synthesis, SAR Development, and in Vivo Efficacy in Cognition Models

A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimers disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.

Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses

Reducing the generation of amyloid-β (Aβ) in the brain via inhibition of β-secretase or inhibition/modulation of γ-secretase has been pursued as a potential disease-modifying treatment for Alzheimers disease. For the discovery and development of β-secretase inhibitors (BACEi), γ-secretase inhibitors (GSI), and γ-secretase modulators (GSM), Aβ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for Aβ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF Aβ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF Aβ lowering is related to that for brain Aβ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF Aβ as an effect biomarker for brain Aβ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of Aβ lowering in the brain.

An Improved System for the Aqueous Lipshutz-Negishi Cross-Coupling of Alkyl Halides with Aryl Electrophiles.

The development of a palladacyclic precatalyst supported by a new biaryl(dialkyl)phosphine ligand (VPhos) in combination with octanoic acid/sodium octanoate as a simple and effective surfactant system provided an improved catalyst system for the rapid construction of a broad spectrum of alkylated scaffolds from alkyl zinc reagents generated in situ.

Cerebrospinal fluid β-Amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses.

Background: Reducing brain β-amyloid (Aβ) via inhibition of β-secretase, or inhibition/modulation of γ-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimers disease. Compounds that act through these mechanisms have been screened and characterized with Aβ lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Aβ turnover process in these compartments. Objective: To understand Aβ turnover kinetics in preclinical species and humans. Methods: We collected CSF Aβ dynamic data after β- or γ-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Aβ turnover rates (kout) in the mouse, dog, monkey and human. Results: The kout for CSF Aβ40 follows allometry (kout = 0.395 × body weight-0.351). The kout for CSF Aβ40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable. Conclusion: The turnover of CSF Aβ40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Aβ in rodents may be different from those in the higher species. The understanding of Aβ turnover has considerable implications for the discovery and development of Aβ-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation.

A convergent process to C-2 substituted peneme via addition of thiols and organocuprates to an O-triflylthioketene acetal

Abstract The synthesis of fully protected penem derivatives has been achieved by addition of thiols and both higher and lower order cuprates to a novel 2-O-trifylpenem.

Diastereoselective Synthesis of 2,3,6-Trisubstituted Piperidines

We report the diastereoselective and chromatography-free syntheses of four 2-phenyl-6-alkyl-3-aminopiperidines. Ring construction was accomplished through a nitro-Mannich reaction linking a nitroketone and phenylmethanimine, followed by a ring-closure condensation. Relative stereocontrol was achieved between C-2 and C-3 by kinetic protonation of a nitronate or by equilibration of the nitro group under thermodynamic control. Stereocontrol at C-6 was accomplished by utilizing a variety of imine reduction methods. The C-2/C-6-cis stereochemistry was established via triacetoxyborohydride iminium ion reduction, whereas the trans relationship was set either by triethylsilane/TFA acyliminium ion reduction or by Lewis acid catalyzed imine reduction with lithium aluminum hydride.

A novel BACE inhibitor (PF-05297909): A two-part adaptive design to evaluate safety, pharmacokinetics and pharmacodynamics for modifying beta-amyloid in a first-in-human study

BackgroundThe accumulation of amyloid beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration seen in the Alzheimers disease (AD) brain. Given the central role of Aβ42 in AD pathogenesis, a therapeutic strategy to lower central Aβ42 (and Aβ40) levels via inhibition of BACE was adopted in a first in human trial in a 2-part adaptive design.MethodsPart 1 evaluated PF-05297909 plasma PK and the PK/PD relationship for the reduction of plasma Aβ40, Aβ42 and AβX levels; Part 2 evaluated the exposure-response relationship between PF-05297909 and CSF levels of Aβ40, Aβ42 and AβX. Sufficient safety and tolerability, plasma exposure and reduction in plasma Aβ were necessary to initiate Part 2. Part 1 was a sequential parallel group dose escalation (25, 100, 250 and 325 mg) with n=8 (6:2, active:placebo) healthy volunteers (HV) in each cohort. Part 2 consisted of 3 cohorts of n=8 (6:2, active:placebo) HV. Doses selected for Part 2 started with the highest safe dose in Part 1 and then adapted for subsequent cohorts. The PK/PD relationship between PF-05297909 and Aβ42 was determined using a non-linear mixed effects (NLME) analysis. The doses for Part 2 - cohort 2 and 3 were to be chosen to improve the relative standard error in the estimate of the BACE IC50 as quantified by evaluating the determinant of the Fisher information matrix for the NLME model.ResultsPF-05297909 was well-tolerated. Reduction in plasma Aβ (Aβ40 and Aβ42) was exposure related with an apparent maximum at the 250 mg dose with a greater duration of activity at the 325 mg dose of PF-05297909. A 325 mg dose was selected for Part 2 - cohorts 1 and 2 without further cohorts being run, as stopping criteria for futility were met following analysis of cohort 2. A PK/PD relationship in CSF was not observed.ConclusionsThe adaptive designed PF-05297909 FIH study allowed efficient testing of safety and of the PK/PD relationship between PF-05297909 exposure and Aβ (Aβ40 and Aβ42). PF-05297909 was safe and well tolerated in HV at exposures tested. A robust effect on plasma Aβ did not translate to CSF pharmacodynamic effects.

Cross-species analysis of cerebrospinal fluid (CSF) beta-amyloid reductions by the BACE1 inhibitor PF-05297909 indicates species differences in PK/PD relationships: Relevance to clinical translation

reversed Ab oligomer-damaged long-term potentiation (LTP) at concentrations that did not interfere normal high frequency stimulation-induced LTP. Moreover, bis(heptyl)-cognitin prevented Ab oligomer-induced reduction of neurite length and synaptic quantity in mature hippocampal neurons. In contrast, tacrine could not reverse synaptic impairments in these models. Under oligomerization condition, bis(heptyl)-cognitin reduced the amount of Ab oligomer as evidenced by dot blot assay and immunoblot analysis. Finally, bis(heptyl)-cognitin was shown to alter Ab self-assembling as demonstrated by circular dichroism spectroscopy and transmission electron microscopy. Conclusions: All these results not only offer a modality as to how dimeric agents protect against Ab oligomer-induced synaptic impairments, but also offers a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.

Significant reduction of brain and CSF amyloid-β in mice following acute administration of a brain-penetrant BACE1 inhibitor

measures (in vitro-in vivo correlation, IVIVC) and identified the best IVIVC, and (3) analyzed the best IVIVC quantitatively to understand in vitro-in vivo translation. Results: Within the potency range of up to 2500 nM, the WT-WCA and mutant-WCA IC50’s are modestly correlated (R 1⁄4 0.8); both of them are only weakly correlated with EAA IC50 (R < 0.45). The IVIVC inspection found that free brain drug exposure (Cb,u) is more relevant than total brain exposure and that the EAA IC50 best predicts in vivo effect of brain Ab reduction. Further quantitative analyses of the brain Ab-Cb,u/EAA IC50 correlation suggested that the maximum brain Ab reduction under those experimental settings was about 70% and that 50% of reduction from baseline was achieved at Cb,u equivalent to EAA IC50. Conclusions: An IVIVC has been established among brain Ab reduction, free brain drug exposure, and enzyme activity assay IC50. This correlation is instrumental in expediting early discovery of BACE1 inhibitors.