Dissecting the Gilles de la Tourette spectrum: a factor analytic study on 639 patients.

BACKGROUND: Recent studies using quantitative methods, such as principal component factor analysis, hierarchical cluster analysis and latent class analysis have suggested that Gilles de la Tourette syndrome (GTS) should no longer be considered a unitary condition as in current classification systems. OBJECTIVE: To identify quantitative components of GTS symptomatology using a large, well characterised cohort of singleton individuals with GTS in order to inform future genetic studies with more homogeneous phenotypes. METHODS: Principal component factor analysis with oblique rotation was used to analyse symptom data from a sample of 639 patients recruited at two tertiary referral centres using identical schedules during the period 1980-2008. RESULTS: Three Factors were identified: (1) complex motor tics and echo-paliphenomena; (2) attention deficit and hyperactivity symptoms plus aggressive behaviours; and (3) complex vocal tics and coprophenomena. Obsessive compulsive behaviours loaded significantly on the first two factors. The three factors accounted for 48.5% of the total symptomatic variance. CONCLUSIONS: GTS is a phenotypically heterogeneous condition encompassing simple tics, specific complex tics and associated behavioural problems. The results, coupled with previous findings, identified a clinical continuum of complex tics, hyperactivity/impulsivity symptoms and semantically relevant utterances and gestures. A better characterisation of the GTS phenotypes will help to identify susceptibility genes.

Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif.

Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.

SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition.

The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.

The behavioral and neurochemical effects of a novel D-amino acid oxidase inhibitor compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and D-serine.

Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC(50), 145 nM) and rat (IC(50), 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by approximately 96% and brain DAAO activity by approximately 80%. This marked decrease in DAAO activity resulted in a significant (p < 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.

Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.

The discovery of fused pyrrole carboxylic acids as novel, potent D-amino acid oxidase (DAO) inhibitors.

The 'NMDA hypofunction hypothesis of schizophrenia' can be tested in a number of ways. DAO is the enzyme primarily responsible for the metabolism of d-serine, a co-agonist for the NMDA receptor. We identified novel DAO inhibitors, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing ip to rats. In parallel, analogues were prepared to survey the SARs of 1.

Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).

We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.

Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors.

In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.

The use of skilled strategies in social interactions by groups high and low in self-reported social skill.

Individuals high or low in self-reported social skill were recruited opportunistically. When presented with everyday social scenarios ending with an awkward request or offer, the high social skill participants more often used sophisticated strategies that showed greater consideration for all parties. By contrast, the low skill participants were more reliant on simple strategies including acquiescence or refusal, and the emotional tone of their responses was less positive. Greater reliance on sophisticated rather than simple strategies may be linked to more successful social interactions. The potential implications are considered for understanding everyday performance in skilled individuals and populations with limited social skills, such as those with autistic spectrum disorders.

Emotional processing and executive functioning in children and adults with Tourette's syndrome.

Tourette's syndrome (TS) is predominantly a childhood disorder, with many of those who meet diagnostic criteria in childhood experiencing a remission of symptoms in adulthood. This indicates that the influence of TS on cognitive and emotional processing can best be understood by examining performance in both adults and children with TS. The present study examined emotional processing using a battery of face and prosody tasks with increasing levels of difficulty (same-different emotion discrimination, emotion naming, and emotion naming with conflict for prosody only). Experiment 1 compared the performance of children with TS-alone (n = 16) or TS+ADHD (n = 15) to healthy matched control children (n = 27). Compared to healthy control children, no significant group differences were found for those with TS-alone. Children with TS+ADHD showed subtle impairments on the more difficult emotion processing tasks relative to healthy control children, and differences were more pronounced for anger items (voice emotion naming, p < .05; voice emotion naming with conflict, p < .01). Experiment 2 compared the performance of adults with TS-alone (n = 23) to healthy matched controls (n = 21). No significant group differences were found, other than evidence of subtle impairment in the adults with TS-alone on the most complex task, again particularly for anger items (p < .05). Separate measurement of executive skills detected no evidence of impairment in children or adults with TS and little in the way of correlational evidence linking emotion recognition and executive skills. Implications of the findings for our understanding of emotion processing in TS are discussed.

Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses.

Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.

Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors.

This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.

Discovery and evaluation of 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as a novel class of KDR kinase inhibitors.

We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.