Susan F. Vice

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease☆

Alzheimers disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides ☆

The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.

Mild N-dealkylation of tertiary, benzylic amines with acid chlorides: Application to solid-phase chemistry

Abstract A mild, facile cleavage of appropriately substituted tertiary, benzylic amines with acid chlorides is described for both solution and solid phase.

Oximino-piperidino-piperidine-based CCR5 antagonists. Part 2: Synthesis, SAR and biological evaluation of symmetrical heteroaryl carboxamides

The synthesis, SAR and biological evaluation of symmetrical amide analogues of our clinical candidate SCH 351125 are described. A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and 2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor.

Indolocarbazole nitrogens linked by three-atom bridges : a potent new class of PKC inhibitors

Abstract Two different approaches to preparing a series of potent PKC inhibitors, represented by 11, are delineated, namely, (a) reaction of indolocarbazole derivatives with appropriate 3-atom synthons followed by hydrolysis and/or hydrolysis/reduction or (b) treatment of 2-TIPS Arcyriaflavin A 10 with apropriate 3-atom synthons proceeded by NSi bond cleavage.

Synthesis and structure–Activity relationships of M2-Selective muscarinic receptor ligands in the 1-[4-(4-Arylsulfonyl)-phenylmethyl]-4-(4-piperidinyl)-piperazine family

The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.

New reactions of hydrazides. Part 1: Directed ortho- and lateral metalation of aromatic carbocyclic and heterocyclic systems

Abstract Aromatic and heterocyclic 2,2-dialkylhydrazides undergo directed metalation with 2 equivalents of n -, s - or t -BuLi, and the resulting C,N-dilithio species react with a variety of electrophiles. The products may be readily converted to the corresponding carboxylic acids or esters by oxidation with manganese dioxide in water or methanol containing acetic acid.

Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene ketal M2 muscarinic receptor antagonists via benzamide modification

We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.