Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P‐gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (Cmax), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2‐fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug‐drug interaction (DDI) with increasing RI severity, a similar 3.1‐fold to 4.4‐fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1‐fold to 4.7‐fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P‐gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst‐case scenario for clinically derisking P‐gp and BCRP substrates in the setting of RI.

No abstract

We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.

No abstract

No abstract

The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.

We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.

We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.KEYWORDS MK-5046, bombesin receptor subtype-3 agonist, obesity T he mammalian bombesin G-protein-coupled receptor subfamily 1 comprises three structurally related members, the receptors for neuromedin B (NMBR or BB1), gastrin-releasing peptide (GRPR or BB2), 2 and bombesin receptor subtype-3 (BRS-3 or BB3). 3 BRS-3 is an orphan receptor whose natural ligand is not known and which, despite its name, does not bind bombesin with high affinity. BRS-3 is expressed predominantly in the central nervous system (CNS). Mice lacking functional BRS-3 develop mild obesity and insulin resistance, suggesting a role for the receptor in the regulation of energy homeostasis. 4 In addition, BRS-3 as well as the other mammalian family members are expressed by several human carcinoma cell lines, where they may play a role in growth regulation. 3 Until recently, there have been limited reports of peptide 5 or smallmolecule 6-9 pharmacological tools to further elucidate the role of the receptor and determine its potential as a drug target.Our laboratory has described the lead identification and initial optimization of the first reported series of smallmolecule BRS-3 agonists with efficacy in body weight lowering. [10][11][12] Exploratory medicinal chemistry efforts focused on lead 1. The potency at the human receptor was improved through the incorporation of branched substituents at the 4-position of the imidazole, while systemic and CNS exposure were increased through replacement of the benzoic acid moiety with pyridine. This work eventually led to the identification of 2 (Bag-1), the first key pharmacological tool in our program. Results of in vivo testing with this compound furnished a preclinical proof of concept for the BRS-3 mechanism: Administration of the BRS-3 agonist in established diet-induced obese (eDIO) mice caused a significant reduction of acute food intake and increase in fasting metabolic rate, and these effects were not evident in Brs3 null (KO) mice. 13 Furthermore, subchronic dosing (100 mpk BID, 8 days) led to mechanism-based body weight lowering in eDIO mice, while it had no significant effects in KO mice. 13 Undesirable features of 2 were its poor oral pharmacokinetics in preclinical species and a suboptimal off-target profile that included low micromolar binding to the human inward rectifying potassium ion channel (hERG, IC 50 = 1.2 μM) as well as the diltiazem (DLZ) site of the rabbit calcium ion channel (IC 50 = 0.5 μM).The low unbound exposure of compound 2 was shown to be due primarily to high intrinsic clearance. A bile duct cannulated rat study was performed to examine the fate of the compound after in vivo dosing. For this purpose, a tritium radiolabel was incorporated in the 5-position of th...