1,3-diaminopropan-2-ol sulfonamides as potent and selective inhibitors of the glycine transporter type 1.

High throughput screening led to the discovery of a novel series of 1,3-diaminopropan-2-ol sulfonamides as selective GlyT-1 inhibitors. Structure-activity relationships of this novel series and optimisation of the initial hit that led to the identification of (2), a potent and selective GlyT-1 inhibitor, are also presented.

High frequency acoustic parameters of human and bovine articular cartilage following experimentally-induced matrix degradation.

Matrix degradation and proteoglycan loss in articular cartilag eare features of early osteoarthritis. To determine the effect of matrix degradation and proteoglycan loss on ultrasound propagation in cartilage, we used papain and interleukin-1alpha to degrade the matrix proteoglycans of human and bovine cartilage samples, respectively. There is also minor collagen alteration associated with these chemical degradation methods.

Phenyl benzenesulfonamides are novel and selective 5-HT6 antagonists: identification of N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134).

Substituted N-phenyl-4-methoxy-3-piperazin-1-ylbenzenesulfonamides and conformationally restricted analogues have been identified as high affinity and selective 5-HT6 antagonists. Compounds from this series had a range of pharmacokinetic profiles in rat and in general there was a correlation between clearance and CNS penetration. Based on its overall biological profile 2 (SB-357134) was selected for further pre-clinical evaluation.