Jeffrey L. Ives

Optimization of a natural product-based class of γ-secretase modulators.

A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Aβ42 levels.

Chapter 3. Antidepressant Agents

Publisher Summary This chapter discusses the several recent reviews that cover various aspects of depression and antidepressant research. The research on selective inhibitors of serotonin (5HT) uptake relative to their effects on the uptake of dopamine (DA) or norepinephrine (NE) has led to the successful development of selective serotonin reuptake inhibitors (SRIs) as antidepressants. The results with fluoxetine seem to characterize the SRIs as a whole, efficacy equivalent to tricyclic antidepressants (TCAs), but often with better toleration because of a different spectrum of side effects. The advantage offered by fluoxetine, therefore, relates to a more benign side effect profile that makes it a more useful agent for some depressed patients. Semaline has proven to be a well tolerated and efficacious antidepressant in a number of trials and its preclinical biology has been reviewed. Paroxetine, one of the more potent 5HT uptake inhibitors in vitro , has shown antidepressant activity in a controlled clinical trial. It is also observed that SRIs produce positive results in treating obsessive compulsive disorder. Although one of the oldest classes of antidepressants, irreversible monoamine oxidase inhibitors (MAO), such as phenelzine and tranylcypromine, have had limited use because of a severe hypertensive crisis. However, recent reviews have appeared that cover the current biological understanding of MAO and the role of MAO inhibition in the treatment of depression. Current research now suggests that reversible and selective inhibition of MAO-A will afford antidepressant activity without hypertensive side effects. Buspirone, gepirone, SM-3997, and ipsapirone represent a new class of non-benzodiazepine anxiolytics that have also demonstrated promise as antidepressants. Further reports on rolipram, the prototype of this new class of antidepressants, have been encouraging. The potential for new therapies of depression and affective disorders has emerged from research around lithium, corticotropin-releasing factor (CRF), and S-adenosyl methionine.

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.

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.

CP-93,129: A Potent and Selective Agonist for the Serotonin (5-HT1B) Receptor and Rotationally Restricted Analog of RU-24,969

The in vitro and in vivo characteristics of CP-93,129 [Structure 1 in Figure 1, 3-(1,2,5,6-tetrahydropyrid-4-yl)-pyrrolo[3,2-b]pyrid-5-one] are described. This rotationally restricted phenolic analog of RU-24,969 is a potent (15 nm) and selective (200 × vs. the 5-HT1A receptor, 150 × vs. the 5-HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of CP-93, I29 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regularing feeding behavior in rodents. CP-93,129 has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. The source of the selectivity of CP-93,129 appears to lie in the ability of a pyrrolo[3,2-b]pyrid5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.

Chapter 6. Cotransmitters in the CNS

Publisher Summary This chapter discusses the examples of the coexistence of neurotransmitters in the central nervous system (CNS). One of the most extensively studied cotransmitter relationships is that of dopamine (DA) with peptides related to cholecystokinin (CCK), a 33 amino acid peptide originally isolated from the gastrointestinal (GI) tract, where it induces pancreatic enzyme secretion. CCK is present in high concentrations in many brain regions, primarily as a sulfated octapeptide (CCK8). Using indirect immunofluorescence histochemistry together with retrograde tracing of fluorescent dyes, CCKB was shown to coexist with DA in the cell bodies and nerve terminals of a subpopulation of mesencephalic neurons. Thus, CCK may have a role in both the etiology and treatment of schizophrenia that could be related to its coexistence with DA. Norepinephrine (NE) has long been known to coexist with somatostatin in the peripheral nervous system (PNS) and with enkephalin in the PNS, CNS (locus coeruleus), and the adrenal medulla. Coexistence has also been demonstrated in the mammalian PNS and CNS with avian- and bovine-pancreatic polypeptide-like material. An area of substantial research has been the investigation of the coexistence of serotonin (5-HT) with substance P (SP) and thyrotropin-releasing hormone (TRH) both in the peripheral and central nervous systems. As with other classic neurotransmitters, γ-aminobutyric acid (GABA) has been shown t o coexist with other transmitters and neuropeptides in single neurons. Investigations of the regional localization of peptides have demonstrated a wide distribution of numerous peptides in the CNS with substantial overlap in regions, such as the pituitary and the hypothalamus. The ubiquitous distribution of peptides both in the peripheral and the central nervous systems and their potential implication in neurological diseases may provide opportunities in future drug research for the selective regulation of peptide-modulated neurons.