The proconvulsant effects of the GABAA alpha5 subtype-selective compound RY-080 may not be alpha5-mediated.

RY-080 (ethyl 8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate) is an imidazobenzodiazepine with 40-50-fold higher affinity for the benzodiazepine binding site of alpha5- rather than alpha1-, alpha2- or alpha3-containing GABAA receptors. Previous data describing RY-080 as being convulsant suggests that inverse agonists selective for the alpha5 subtype may not be suitable for clinical development. In the present study, we show that RY-080 possesses inverse agonism for the alpha1 and alpha5 subtypes of human recombinant GABAA receptors and whilst not convulsant it was proconvulsant. Hence, with pentylenetetrazole alone, the dose predicted to give tonic convulsions in 50% of the mice (ED50) was 108 mg/kg whereas in the presence of 1 and 10 mg/kg RY-080, the ED50s were 93 and 57 mg/kg, respectively. In vivo [3H]L-655,708 and [3H]Ro 15-1788 binding assays showed that the subtype selectivity of RY-080 in vivo was 7-10-fold for alpha5-relative to alpha1- and alpha2/alpha3-containing receptors (respective ID50 values of 0.93, 9.7 and 6.2 mg/kg) and is therefore much lower than seen in vitro. Consequently, it is not possible to define a dose of RY-080 which gives high occupancy of the alpha5 subtype without binding to other subtypes and accordingly the proconvulsant effects of RY-080 cannot be attributed solely to the alpha5 subtype.

4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists.

On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.

Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.

Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).

Sarcosine based indandione hGlyT1 inhibitors.

A series of sarcosine based indandione hGlyT1 inhibitors has been developed. Optimization of substitution around the indandione and sarcosine moieties has led to highly potent inhibitors at hGlyT1, which show selectivity over a number of other receptors.