Giuseppe Giardina

γ-secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes.

According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimers disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ secretase shifting its cleavage activity from longer to shorter β-amyloid species without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aβ brain pathology and learning depend on their activity on γ-secretase or on other biological targets. The most studied γ-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aβ in the cerebrospinal fluid of healthy humans. Unfortunately, two large Phase 3 clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of APP, or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R flurbiprofen), a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch-sparing γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks.

The opioid-receptor-like 1 (ORL-1) as a potential target for new analgesics.

Anew sequence, which encoded a novel G protein-coupled receptor, was disclosed by two different groups, using the nucleic acid probes based on the delta opioid receptor, first cloned in 1992. The new receptor, which Meunier called opioid-receptor-like 1 (ORL-1), was shown to share high homology with the opioid receptors and therefore thought to be a potential target for new analgesics. In this respect, the present review reports on the literature referring to ORL-1, to its natural ligand (nociceptin or orphanin FQ) and to several synthetic analogues recently described, both as agonists or antagonists at the receptor.

A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one(J-113397), the first non-peptide ORL-1 receptor antagonist..

An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397) 1, the first non-peptide ORL-1 receptor antagonist described in literature, is outlined. After construction of the piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, condensation with o-phenylendiamine produced the beta-enamino ester 2, which has been conveniently used to construct the benzimidazolone substituent at C-4. Catalytic hydrogenation of intermediate 11 followed by base-promoted cis--trans isomerization of the key compound 12 led to the formation of ester 13, which was converted to the racemic title compound by LiAlH(4) reduction. The pure enantiomers were obtained by chiral preparative HPLC separation using a derivatized cellulose-based stationary phase.

Lead generation and lead optimisation approaches in the discovery of selective, non-peptide ORL-1 receptor agonists and antagonists

The discovery of the opioid receptor like-1 (ORL-1) receptor and of its endogenous agonist nociceptin/orphanin FQ has attracted great interest in the scientific community giving rise, in the last five years, to a flurry of biological studies aimed at elucidating the role of this new receptor. Hence, the involvement of the ORL-1 receptor in many important processes, such as antinociception, learning and memory, feeding and anxiety, has been well documented. However, a clear understanding of the potential therapeutic value associated with the modulation of the ORL-1 receptor needs the development of selective non-peptide agonists and antagonists allowing systemic routes of administration. This review addresses the advances made by several research groups in the discovery of such compounds and discusses the medicinal chemistry strategies which, starting from the first non-selective ligands NalBzoH and lofentanil, led to the disclosure of highly potent and selective agonists and antagonists, such as Ro 64-6198, J-113397 and JTC-801. Efforts have also focussed on the pharmacological characterisation of the newly discovered non-peptide tools, which represent a significant step forward in the understanding of the involvement of the ORL-1 receptor in a number of possible pathophysiological conditions.

Replacement of the quinoline system in 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonists.

Results from a medicinal chemistry approach aimed at replacing the quinoline ring system in the potent and selective human neurokinin-3 (hNK-3) receptor antagonists 1-4 of general formula I are discussed. The data give further insight upon the potential NK-3 pharmacophore. In particular, it is highlighted that both the benzene-condensed ring and the quinoline nitrogen are crucial determinants for optimal binding affinity to the hNK-3 receptor. Some novel compounds maintained part of the binding affinity to the receptor (5, 6, 10 and 13) and compound 5, featuring the naphthalene ring system, appears to be suitable for further modifications; it offers the option to introduce electron-withdrawing groups at position 2 and 4, conferring on the ring an overall electron-deficiency similar to that of the quinoline.

Selective δ opioid receptor agonists for inflammatory and neuropathic pain

In the last decade a number of selective and potent non-peptidic agents became available to explore the usefulness of the δ-opioid receptor in modulation of pain of different origins. As a continuing effort in this field, potent and selective δ-opioid agonists based on the pyrrolomorphinan framework have been designed, synthesised and characterised biologically in our laboratories. In animal models, a selected compound of interest, SB 235863, has proved the concept that selective δ-opioid agonists may have great potential as pain relief agents in inflammatory and neuropathic pain conditions. Importantly, such a compound was free of the unwanted side effects usually associated with narcotic analgesics such as morphine.

Recent advances in neurokinin-3 receptor antagonists

This review addresses the recent highlights and progress made in the neurokinin-3 (NK-3) receptor area since the last update, provided in this journal in 1997. Whereas in the neurokinin-1 (NK-1) and neurokinin-2 (NK-2) biological areas literature information based on clinical data account for a high therapeutic potential (in emesis and depression for NK-1 and asthma for NK-2 receptor antagonists), there is a total deficiency of information from NK-3 receptor antagonists in clinical development. No other chemical classes in addition to dichlorophenylalkylpiperidines, represented by SR 142,801 and quinolines, represented by SB-222200 and SB-223412, have been identified by pharmaceutical companies and scientists involved in the specific field. Biological evidence indicates pain/inflammation as a suitable CNS-related therapeutic target, this conclusion is based on localisation studies and efficacy of selected NK-3 receptor antagonists in rat disease models of inflammatory pain. In the periphery, the most likely therapeutic indications might be pulmonary and gastrointestinal tract diseases. It is clearly still premature to anticipate any therapeutic potential in man.

A reliable and efficient synthesis of SR 142801

Abstract A convenient synthesis of the potent human NK-3 receptor antagonist SR 142801, (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl}-4-phenylpiperidin-4-yl}-N-methylacetamide [(S)-(+)-(15)], is described. Improvements over the previously reported procedure are the preparation of the intermediate 5 via the novel imide 3 and subsequent reaction with the nucleophile 14, which reacts, regioselectively, at the endocyclic nitrogen.

Neurokinin-3 receptor antagonists

Until late 1994, research on the neurokinin-3 (NK3) receptor, compared with that on neurokinin-1 (NK1) and neurokinin-2 (NK2) receptors, received little attention, due, to a large extent, to the absence of potent and selective non-peptide NK3 receptor antagonists. During 1995 and 1996, the disclosure of non-peptide antagonists led to a marked increase in research activities aimed at clarifying the physiological and pathophysiological role of the NK3 receptor. This review addresses the recent highlights and developments in this area, with particular emphasis on non-peptide NK3 receptor antagonists. Focus has been given to the various strategies utilised by several pharmaceutical companies to identify NK3 receptor antagonist prototypes and on the chemical optimisation processes which led to the potent and selective peptide-derived PD 161182 (8), the dichlorophenylalkylpiperidine SR 142,801 (9) and the quinoline derivative SB 223412 (27), which are representative compounds of the three distinct chemical clas...

Molecular and pharmacological characterization of the murine tachykinin NK3 receptor

Starting with a partial sequence from Genbank, polymerase chain reaction (PCR) was utilized to isolate the full-length cDNA for NK(3) receptor from mouse brain. The murine NK(3) receptor has a predicted sequence of 452 amino acids, sharing 96% and 86% identity to the rat and human NK(3) receptors, respectively. Binding affinities and functional potencies of tachykinin receptor agonists were similar in HEK (human embryonic kidney) 293 cells expressing murine NK(3) receptor and human NK(3) receptor, although substance P and neurokinin A were more potent stimulators of Ca(2+) mobilization in murine NK(3) receptor cells. NK(3) receptor-selective antagonists from two structural classes, had 10- to 100-fold lower binding affinities for murine NK(3) receptor compared to human NK(3) receptor, and about 5- to 10-fold reduced potency in the murine NK(3) receptor functional assay. The results demonstrate species differences in the potencies of tachykinin receptor antagonists in murine and human NK(3) receptors, and the lower potencies in the former should be taken into consideration when using murine disease models.