Discovery of Molidustat (BAY†85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia.

Small-molecule inhibitors of hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment options for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased erythropoietin (EPO) expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, structure-activity relationship (SAR), and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia. High-throughput screening of our corporate compound library identified BAY-908 as a promising hit. The lead optimization program then resulted in the identification of molidustat (BAY 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phase III trials as molidustat sodium for the treatment of anemia in patients with CKD.

Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects.

Oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) is the dominant regulatory mechanism of erythropoietin (EPO) expression. In chronic kidney disease (CKD), impaired EPO expression causes anemia, which can be treated by supplementation with recombinant human EPO (rhEPO). However, treatment can result in rhEPO levels greatly exceeding the normal physiological range for endogenous EPO, and there is evidence that this contributes to hypertension in patients with CKD. Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

Synthesis of all 16 stereoisomers of pinesaw fly sex pheromones--tools and tactics for solving problems in fluorous mixture synthesis.

[Reaction: see text]. The application of fluorous mixture synthesis (FMS) for accessing natural products and their stereoisomers was validated by the total synthesis of all 16 stereoisomers of the pine sawfly sex pheromone. Four fluorous p-methoxybenzyl groups were used as tags, and a "4-mix-4-split" approach was employed in a divergent synthesis. This paper presents the details of the FMS of pine sawfly sex pheromones with an emphasis on identification and solving of problems encountered when working with fluorous mixtures.

Stereoisomer libraries: total synthesis of all 16 stereoisomers of the pine sawfly sex pheromone by a fluorous mixture-synthesis approach.

All 16 stereoisomers of the sex pheromone of pine sawfly (3,7,11-trimethylundecanol propanoate ester) have been synthesized on a 10- to 20-mg scale by a split-parallel fluorous mixture-synthesis approach. Spectral data obtained for all 32 compounds (16 alcohols and the corresponding propionates) matched well with published data, thereby validating the fluorous-tag encoding of diastereoisomers. This fluorous-tag encoding method is recommended for the efficient synthesis of multiple stereoisomers for spectroscopic studies, biological tests, or other structure-function relationships.