Ellen W. Baxter

ARYLSULFONATE ESTERS IN SOLID PHASE ORGANIC SYNTHESIS. I. CLEAVAGE WITH AMINES, THIOLATE, AND IMIDAZOLE

Abstract The arylsulfonate ester functionality connecting an alkyl chain to a polystyrene resin is cleaved with neat volatile primary or secondary amines to give secondary or tertiary amines, respectively, in high yields and purity. Non-volatile secondary amines, thiols, and imidazole also cleave the alkyl chain efficiently to afford the expected products which can be readily purified by an ion-exchange resin work-up method.

Arylsulfonate esters in solid phase organic synthesis. II. Compatibility with commonly-used reaction conditions

Abstract The arylsulfonate ester functionality connecting an alkyl chain to a polystyrene resin is compatible with Grignard additions, stabilized Wittig, sodium borohydride reduction, reductive aminations, acylations and addition of various electrophiles, and Suzuki coupling. Cleavage of the resin-bound substrate with amines and other nucleophiles can provide diverse compound libraries.

Emerging β-amyloid therapies for the treatment of Alzheimer's Disease

Alzheimers Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of β-amyloid peptide (Aβ) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the “amyloid cascade hypothesis” of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic β-amyloid (Aβ) aggregates, all FAD mutations increase levels of Aβ peptide or density of Aβ deposits. The likely link between Aβ aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Aβ production. This review summarizes current therapeutic strategies directed at lowering Aβ levels and decreasing levels of toxic Aβ aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Aβ peptide, (2) inhibition, reversal or clearance of Aβ aggregation, (3) cholesterol reduction and (4) Aβ immunization.

Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.

We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimers disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).

Concise synthesis of 1-deoxymannojirimycin

Abstract The synthesis of 1-deoxymannojirimycin ( 1 ) is readily achieved in four steps from 1-methyl-2,3-isopropylidene- d -mannofuranoside ( 2 ). The key step is a double reductive amination of 5-keto- d -mannose ( 3 ) using NaBH 3 CN, entailing a marked divergence in stereocontrol relative to the reported use of catalytic methods. The important enzyme inhibitor 1-deoxymannojirimycin ( 1 ) was prepared from 5-keto- D -mannose ( 3 ) in two steps. The key double reductive amination displays a marked divergence in stereocontrol relative to that reported for similar reactions performed under catalytic conditions.

The synthesis and evaluation of the major metabolites of mazapertine

Several of the key metabolites of mazapertine, a novel antipyschotic agent, were prepared in order to firmly establish their chemical structure and to obtain samples for biological testing. Hydroxymazapertine 3 was synthesized via a multi-step procedure starting from 5-fluoro-2-nitrophenol (8). Alcohol 4 was originally proposed for one of the major metabolites, but the confirmed structure after synthesis was isomer 20.

Hindered rotation congeners of mazapertine: High affinity ligands for the 5-HT1A receptor

Abstract Hindered rotation analogs of the antipsychotic mazapertine (1) were prepared. These compounds exhibited high affinity for the HT-1A receptor, but not for other serotonin or dopamine receptors. The related β-carboline structures were also sybthetized and were found to be potent 5-HT1A ligands.

α1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms

Background: Although α1 adrenergic receptor blockers can be very effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature of many current drugs. To overcome this problem, it was hypothesized that an α1a/1d subtype selective antagonist would be efficacious yet produce less side effects, and hence would bring greater benefit for the therapy of BPH/LUTS. Unfortunately, such highly selective α1a/1d antagonists were not available, making the validation of the new hypothesis impossible. Objective/method: This review disclosed several series of α1a/1d subtype selective antagonists that have been discovered and developed by Johnson & Johnson recently. These compounds show equal and potent affinity for both α1a and α1d subtypes with good selectivity versus the α1b subtype. Some analogues also possess favorable pharmacokinetic properties. Conclusion: Although discovery of α1a/1d subtype selective antagonists paves the way for future research, the effectiveness of α1a/1d subtype selective antagonist in BPH/LUTS patients still needs to be proven in clinical trials. This patent review will focus on the latest progress in this field from 2006 to present.

Piperazinyl benzamidines: synthesis and affinity for the delta opioid receptor.

Piperazinyl benzamidines were prepared and found to bind to the rat delta (delta) opioid receptor. The most active compounds had a N,N-diethylcarboxamido group and a N-benzyl piperazine. The most potent among these was N,N-diethyl-4-[4-(phenylmethyl)-1-piperazinyl][2-(trifluoromethyl)phenyl]iminomethyl]benzamide (27) with a 1.22nM K(i) for the rat delta opioid receptor and ca. 1000 x selectivity relative to the mu opioid subtype.