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Gastroenterology, 2014
10), these ERR slope estimates were less steep than those in the exploratory plots. Within groups... more 10), these ERR slope estimates were less steep than those in the exploratory plots. Within groups, defined by quartiles of baseline covariates between C average values of 32 to 85 μg/ mL (5th and 95th percentiles), the average probability of clinical response and clinical remission increased by 15% and 10%, respectively. On average, patients with lower baseline CRP levels and no prior anti-TNF-α use have a higher probability of clinical remission whether receiving placebo or VDZ. The likelihood ratio statistic of the 2-way interaction analysis was not significantly different for either clinical response (2.49; P=.647) or remission (5.47; P=.243), indicating no dependence of the VDZ ERRs on baseline covariates. Conclusions: A positive ERR exists for both clinical response and clinical remission in patients with CD after 6 weeks of induction therapy with VDZ 300 mg; however, any ERR derived from plots or tables of observed data may provide an overestimation of the true VDZ ERR. Furthermore, the VDZ ERR was not found to be dependent on any of the covariates tested.
Journal of Medicinal Chemistry, 2014
FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is inv... more FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.
The Journal of Immunology, 2013
Gastroenterology, 2014
10), these ERR slope estimates were less steep than those in the exploratory plots. Within groups... more 10), these ERR slope estimates were less steep than those in the exploratory plots. Within groups, defined by quartiles of baseline covariates between C average values of 32 to 85 μg/ mL (5th and 95th percentiles), the average probability of clinical response and clinical remission increased by 15% and 10%, respectively. On average, patients with lower baseline CRP levels and no prior anti-TNF-α use have a higher probability of clinical remission whether receiving placebo or VDZ. The likelihood ratio statistic of the 2-way interaction analysis was not significantly different for either clinical response (2.49; P=.647) or remission (5.47; P=.243), indicating no dependence of the VDZ ERRs on baseline covariates. Conclusions: A positive ERR exists for both clinical response and clinical remission in patients with CD after 6 weeks of induction therapy with VDZ 300 mg; however, any ERR derived from plots or tables of observed data may provide an overestimation of the true VDZ ERR. Furthermore, the VDZ ERR was not found to be dependent on any of the covariates tested.
Journal of Medicinal Chemistry, 2014
FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is inv... more FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.
The Journal of Immunology, 2013