Tamara Ladduwahetty

Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets

These studies have compared the pharmacological profile of two non-peptide human type neurokinin1 (hNK1) receptor selective antagonists, L-741,671 and a quaternised compound L-743,310. In radioligand binding studies L-741,671 and L-743,310 had high affinity for ferret and cloned hNK1 receptors [Ki (nM) ferret 0.7 and 0.1; human 0.03 and 0.06, respectively] but low affinity for rodent NK1 receptors [Ki (nM) 64 and 17, respectively] suggesting that ferret receptors have hNK1-like binding pharmacology. Studies in vivo showed that L-741,671 and L-743,310 had equivalent functional activity in the periphery (ID50s of 1.6 and 2 micrograms/kg i.v., respectively) as measured by inhibition of plasma protein extravasation evoked in the oesophagus of guinea pigs by resiniferatoxin (7 nmol/kg i.v.). Using an in situ brain perfusion technique in anaesthetised rats, L-741,671 was shown to be much more brain penetrant than the quaternary compound L-743,310 which had an entry rate similar to the poorly brain penetrant plasma marker inulin. These compounds thus provided an opportunity to compare the anti-emetic effects of equi-active hNK1 receptor antagonists with and without brain penetration to central NK1 receptor sites. When tested against cisplatin-induced emesis in ferrets, L-741,671 (0.3, 1 and 3 mg/kg i.v.) produced marked dose-dependent inhibition of retching and vomiting but L-743,310 was inactive at 3 and 10 micrograms/kg i.v. In contrast, direct central injection of L-741,671 and L-743,310 (30 micrograms) into the vicinity of the nucleus tractus solitarius or L-743,310 (200 micrograms) intracisternally was shown to inhibit retching and vomiting induced by i.v. cisplatin. L-741,671 and L-743,310 had equivalent functional activity, at the same dose, against cisplatin-induced emesis when injected centrally. These observations indicated that had L-743,310 penetrated into the brain after systemic administration it would have been active in the cisplatin-induced emesis assay and so show that brain penetration is essential for the anti-emetic action of systemically administered NK1 receptor antagonists.

Stereoselectivity in the Birch reduction of 2-furoic acid derivatives

The preparation and Birch reduction of chiral 3-methyl-2-furoic acid derivatives is described. Using a C2 symmetrical amine as a chiral auxiliary, very high levels of sterochemical control could be obtained. Moreover, the auxiliary could be removed conveniently by heating in 6M HCl to liberate a carboxylic acid of high enantiomeric purity. The relative stereochemistry of the Birch reduced amides (and therefore the absolute stereochemistry of the corresponding acids) was determined unambiguously from an X-ray crystal structure.

The synthesis of (−)-cis- and (−)-trans-crobarbatic acid

Abstract The synthesis of both cis- and trans-crobarbatic acid is reported. The five-step sequence proceeds in high yield and with control of both relative and absolute stereochemistry. The key step in the synthesis is the Birch reductive alkylation of a chiral furoic acid which sets the absolute stereochemistry of the products. The stereochemistry of the compounds described was proven unambiguously by X-ray crystallography on one synthetic intermediate and on trans-crobarbatic acid.

A stereoselective synthesis of (±)-actinobolamine

A three-step sequence involving an imino ester heterocycloaddition, stereoselective epoxidation of the adduct 4 and subsequent toluene-p-sulphonic acid-promoted rearrangement afforded the 6-azabicyclo[3.2.1]octane 7 in excellent overall yield; elaboration of this 6-azabicyclo[3.2.1]octane skeleton to (±)-actinobolamine is described.

Effects of five-membered ring conformation on bioreceptor recognition: identification of 3R-amino-1-hydroxy-4R-methylpyrrolidin-2-one (L-687,414) as a potent glycine/N-methyl-D-aspartate receptor antagonist

Syntheses of the 4-methyl (2 and 3) and [3.2.1]bicyclo (4 and 5) analogues of the glycine/N-methyl-D-aspartate (NMDA) antagonist 3-amino-1-hydroxypyrrolidin-2-one (HA-966, 1) provide evidence that glycine receptor recogntion requires the energetically less favoured 3-pseudoaxial conformation of the pyrrolidone ring, resulting in a 5–10 fold improvement in activity with the 3R-amino, 4R-methyl derivative (2a, L-687,414).

4-hydroxyphenoxymethylene bisphosphonic acid derivatives: potent, non-hydrolysable inhibitors of MYO-inositol monophosphatase

Abstract From a series of 4-hydroxyphenoxymethylene bisphosphonic acid derivatives 1-(4-Hydroxyphenoxy)-1-(methyl)methylenebisphosphonic acid has been identified as a structurally simple, competitive, inhibitor of myo -inositol monophosphatase (IC 50 , 0.33 μM). Replacement of the 1-methyl group by a 3-(3,4-dichlorobenzamido)benzyl substituent affords the most potent inhibitor of the series (IC 50 , 0.08 μM).

Stereocontrolled total synthesis of (5Z,8Z11Z,13E)(15S)-15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15S-HETE) and analogues

A novel and stereoselective synthesis of 15S-HETE and a number of analogues based on CuI–Pd0 coupling reaction is described.

Stereoselective reduction of chiral 2-furoic acid derivatives using group I metals in ammonia

A series of chiral auxiliaries have been attached to 2-furoic acid and 3-methyl-2-furoic acid. The performance of these auxiliaries in the Birch reduction was assessed and it was found that placing a C-3 methyl group on the heterocycle was essential for good stereoselectivity. Using bis(methoxymethyl)pyrrolidine high levels of diastereoselectivity could be obtained with a range of electrophiles. A model is also presented which explains the sense of stereoselectivity displayed by this auxiliary. After reduction, the auxiliaries could be removed by reaction with acid to furnish dihydrofuran-based carboxylic acids with high enantiomeric excess.