Stronger Uricosuric Effects of the Novel Selective URAT1 Inhibitor UR-1102 Lowered Plasma Urate in Tufted Capuchin Monkeys to a Greater Extent than Benzbromarone s

ABSTRACT Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3-30 mg/kg or benzbromarone at 3-100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level. When compared with the same dosage of benzbromarone, UR-1102 showed a better pharmacokinetic profile, increased the fractional excretion of urinary uric acid, and reduced plasma uric acid more effectively. Moreover, the maximum efficacy of UR-1102 was twice that of benzbromarone, suggesting that selective inhibition of URAT1 is effective. Additionally UR-1102 showed lower in vitro potential for mechanisms causing the hepatotoxicity induced by benzbromarone. These results indicate that UR-1102 achieves strong uricosuric effects by selectively inhibiting URAT1 over OAT1 and OAT3 in monkeys, and could be a novel therapeutic option for patients with gout or hyperuricemia

Metabolites of alectinib in human: their identification and pharmacological activity

Two metabolites (M4 and M1b) in plasma and four metabolites (M4, M6, M1a and M1b) in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant

iPS-heps vs HepPre48hr_3mix_NormalizedData

Microarray data for iPS cells and iPS cell-derived differentiated cells, iPS cell-derived hepatocytic cells, and primary hepatocytes harvested after 48hr culture (a mixture from 3 samples)

5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity

Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed

Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity: Validation of the Target and Identification of Novel Series

Obesity is a major risk factor for the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. Several pieces of evidence, including data in primates, have demonstrated the beneficial effects of histamine-3 receptor (H 3 R) inverse agonists in the regulation of food intake and body weight. A pharmacophore model based on selected published H 3 R ligands and validated by previ- ous investigations, was used to identify the 5-oxy-2-carboxamide-indole core as a novel series of H 3 R inverse agonists. Extensive structure-activity relationship (SAR) investigations were rewarded by the identification of several compounds reversing ( R )- α -methyl-histamine-induced water intake increase and reducing food intake/ body weight in rodent models of obesity. Among those compounds, (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5- (1-isopropyl-piperidin-4-yloxy)-1 H -indol-2-yl]-methanone, selected as a lead compound, was exhibiting a prom- ising profile, including excellent pharmacokinetic properties, good in vitro safety profile and high efficacy in a chronic rodent model of obesity

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit <b>4a</b>, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1<i>R</i>,4<i>R</i>)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro­[4.5]­dec-1-en-8-yl)­sulfonyl)­ethyl)­phenyl)-1-methylurea (CH5447240, <b>14l</b>). Compound <b>14l</b> exhibited a potent in vitro hPTHR1 agonist effect with EC₂₀ of 3.0 μM and EC₅₀ of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, <b>14l</b> showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit <b>4a</b>, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1<i>R</i>,4<i>R</i>)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro­[4.5]­dec-1-en-8-yl)­sulfonyl)­ethyl)­phenyl)-1-methylurea (CH5447240, <b>14l</b>). Compound <b>14l</b> exhibited a potent in vitro hPTHR1 agonist effect with EC₂₀ of 3.0 μM and EC₅₀ of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, <b>14l</b> showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats