Gregory W. Kauffman

Novel γ-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012

Introduction: γ-Secretase is the enzyme responsible for the final step of amyloid precursor protein proteolysis to generate Aβ peptides including Aβ42 which is believed to be a toxic species involved in Alzheimers disease (AD) progression. γ-Secretase modulators (GSMs) have been shown to selectively lower Aβ42 production without affecting total Aβ levels or the formation of γ-secretase substrate intracellular domains such as APP intracellular domain and Notch intracellular domain. Therefore, GSMs have emerged as an important therapeutic strategy for the treatment of AD. Areas covered: The literature covering novel GSMs will be reviewed focusing on patents from 2010 to 2012. Expert opinion: During the last review period (2008 – 2010) considerable progress was made developing GSMs with improved potency for lowering Aβ42 levels, but most of the compounds resided in unfavorable central nervous system (CNS) drug space. In this review period (2010 – 2012), there is a higher percentage of potent GSM chemical matter that resides in favorable CNS drug space. It is anticipated that clinical candidates will emerge out of this cohort that will be able to test the GSM mechanism of action in the clinic.

Extraction of tacit knowledge from large ADME data sets via pairwise analysis

Pharmaceutical companies routinely collect data across multiple projects for common ADME endpoints. Although at the time of collection the data is intended for use in decision making within a specific project, knowledge can be gained by data mining the entire cross-project data set for patterns of structure-activity relationships (SAR) that may be applied to any project. One such data mining method is pairwise analysis. This method has the advantage of being able to identify small structural changes that lead to significant changes in activity. In this paper, we describe the process for full pairwise analysis of our high-throughput ADME assays routinely used for compound discovery efforts at Pfizer (microsomal clearance, passive membrane permeability, P-gp efflux, and lipophilicity). We also describe multiple strategies for the application of these transforms in a prospective manner during compound design. Finally, a detailed analysis of the activity patterns in pairs of compounds that share the same molecular transformation reveals multiple types of transforms from an SAR perspective. These include bioisosteres, additives, multiplicatives, and a type we call switches as they act to either turn on or turn off an activity.

Novel γ-secretase modulators: a review of patents from 2008 to 2010

Introduction: The amyloid precursor protein is first cleaved by β-secretase to generate a 99-residue membrane-bound CTF (C99 or β-CTF), which is subsequently cleaved by γ-secretase to generate amyloid β (Aβ) peptides and the APP intracellular domain. The amyloidogenic Aβ42 has attracted considerable attention because it is thought to be the most pathogenic species associated with Alzheimers disease progression. New classes of compounds, called γ-secretase modulators (GSMs), have been shown to selectively lower Aβ42 production without shutting down key γ-secretase-dependent signaling pathways. This has become an important therapeutic strategy aimed at modulating Aβ production. Areas covered: The progress on the clinical development of γ-secretase inhibitors is briefly covered in this review, followed by a discussion of the potential differentiating attributes of GSMs. Then, the patent literature covering novel GSMs is reviewed, focusing on patents from 2008 to 2010. Expert opinion: Much progress has been made in the past 2 years on developing GSMs with improved potency for lowering the production of Aβ42. However, many of these chemotypes are in a challenging chemical space and generally possess higher lipophilicity than most CNS drugs. It will be important to gain a better understanding of the specific target(s) that these GSMs interact with in order to facilitate future drug design efforts.

Interpretable, probability-based confidence metric for continuous quantitative structure-activity relationship models.

A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure-activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compounds neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year.

Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active γ-secretase modulators.

We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aβ42 lowering activity at 100 mg/kg po dose.

Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects

It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimers disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.

Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulators.

Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aβ42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the γ-secretase complex, thus gaining insight into the binding site of this series of GSMs.

Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin.

Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.

Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability

Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.

Design and optimization of selective azaindole amide M1 positive allosteric modulators

Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimers disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.