Jed L. Hubbs

Purine derivatives as potent γ-secretase modulators

The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimers disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.

Fluorinated piperidine acetic acids as γ-secretase modulators

We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.

Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models

IntroductionModulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ42 peptide while sparing the production of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimers disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats.MethodsAnimals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS.ResultsIn wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also observed in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF.ConclusionsTaken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimers disease.

Initial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene Glycoside

The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.

Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease

The Amyloid Hypothesis states that the cascade of events associated with Alzheimers disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimers disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aβ 42. Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aβ 42 and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity.

SAR investigations on a novel class of gamma-secretase modulators based on a unique scaffold

In this communication we present details of our analog efforts within a novel series of gamma-secretase modulating compounds. Esters and carbamates were investigated as bioisosteres for a glycoside moiety present in an initial hit isolated from black cohosh extract. We identified elements within each series that retain the potency and selectivity of the initial lead while improving physicochemical properties.

Minimization of drug–drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators

Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate.

Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor.

The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.