Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.

Synthesis of the anti-trypanosomal agent (±)-hydroxyanthecotulide by Cr(ii)-catalysed allylation and Meyer-Schuster rearrangement.

The first synthesis of the bioactive sesquiterpene lactone hydroxyanthecotulide is achieved in 7 steps, involving a stereocontrolled Cr(ii)-catalysed reaction of 3-(bromomethyl)furan-2(5H)-one with enynal 9 and a mild Au(i)-catalysed Meyer-Schuster rearrangement.

Catalytic asymmetric synthesis of (+)-anthecotulide using enyne and Meyer-Schuster rearrangements.

The bioactive sesquiterpene lactone (+)-anthecotulide (1) is synthesized for the first time, in a six-step sequence devoid of protecting groups. The key transformations are a novel Rh(I)-catalyzed asymmetric enyne rearrangement of a terminal alkynyl ester (4), to form the α-methylene-γ-butyrolactone core, and a final-step mild Au(I)-catalyzed Meyer-Schuster rearrangement.

Stereoselective synthesis of β-(hydroxymethylaryl/alkyl)-α-methylene-γ-butyrolactones.

Zinc or a chromium(II) source with 3-(bromomethyl)furan-2(5H)-one (3) and an aldehyde gives β-(hydroxymethylaryl/alkyl)-α-methylene-γ-butyrolactones 5 in good yields and high diastereoselectivities. The methodology is demonstrated in concise syntheses of (±)-hydroxymatairesinol (8) and (±)-methylenolactocin (10) by subsequent arylboronate conjugate addition and translactonization, respectively.

Discovery and structure-activity relationships of novel selective norepinephrine and dual serotonin/norepinephrine reuptake inhibitors.

Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.

The extraordinary reactions of phenyldimethylsilyllithium with N,N-disubstituted amides.

Phenyldimethylsilyllithium reacts with N,N-dimethylamides in a variety of ways, depending upon the stoichiometry, the temperature and, most subtly, on the structure of the amide, with quite small-seeming changes in structure leading to profound changes in the nature of the products. When equimolar amounts of the silyllithium reagent and N,N-dimethylamides 6 are combined in THF at -78 degrees C, and the mixture quenched at -78 degrees C, the product is the corresponding acylsilane . If the same mixture is warmed to -20 degrees C before quenching, the product is a cis enediamine 11.

Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals.

1. Three novel phenylglycine analogues; (RS)-alpha-methyl-3-chloro-4-phosphonophenylglycine (UBP1110), (RS)-alpha-methyl-3-methoxy-4-phosphonophenylglycine (UBP1111) and (RS)-alpha-methyl-3-methyl-4-phosphonophenylglycine (UBP1112) antagonised the depression of the fast component of the dorsal root-evoked ventral root potential induced by (S)-AP4 with apparent K(D) values of: 7.4+/-2.

Enantiomerically pure nucleophiles in diastereoselective palladium catalysed allylic substitution reactions.

Enantiomerically pure alpha-amino esters were applied in palladium catalysed allylic substitution reactions with moderate diastereoselectivity (up to 70% d.e.) using achiral ligands on symmetrical allylic acetates.

Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists.

A series of novel group I metabotropic glutamate receptor (mGlu) antagonists have been designed on the basis of the 4-carboxyphenylglycine pharmacophore. The compounds are either mGlu1 receptor selective or equipotent for both mGlu1 and mGlu5 receptors and have IC(50) values ranging from 1 to 30 microM determined by phosphoinositide hydrolysis (PI) assay in vitro. All the compounds produced dose-dependent inhibition of group I mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced limbic seizure responses in mice with ED(50) values ranging from 9 nmol for LY393053 to 138 nmol for LY339840 after intracerebroventricular injection and were more potent than the mGlu1 receptor antagonist 1-aminoindan-1,5-dicarboxylic acid (ED(50)=477 nmol).

The Role of Type 1 Metabotropic Glutamate Receptors in the Generation of Dorsal Root Reflexes Induced by Acute Arthritis or the Spinal Infusion of 4-Aminopyridine in the Anesthetized Rat.

Antidromically propagated action potentials can be recorded in the proximal end of the severed medial articular nerve (MAN) on mechanical stimulation of an inflamed knee in rats and are referred to as dorsal root reflex (DRR) activity. The absence of DRR activity in normal rats suggests that the activity could be the result of hyperexcitability of spinal neurons induced by inflammation. In this study, the role of spinal type 1 metabotropic glutamate (mGlu(1)) receptors in the generation of DRR activity in the MAN during acute knee inflammation was investigated.