RESUMO
Selective progesterone receptor modulators are promising therapeutic options for the treatment of uterine fibroids. Vilaprisan, a new chemical entity that was discovered at Bayer is currently in clinical development. In this study we provide a combined experimental and quantum chemical approach providing the data that allowed to present hydroxyestradienone as an acceptable starting material for drug substance synthesis. Hydroxyestradienone has four stereogenic centers leading to 8 diastereomers and 16 enantiomers of which only six diastereomers were synthetically accessible but two not. A computational multistep protocol resulting in density functional P2PLYP-D3(BJ)/dev2-TZVPP Gibbs free energies and SMD solvation free energies led to a clear separation between the existing and the synthetically not accessible enantiomers, whereas multiple geometry-based and cheminformatic descriptors were not able to explain experimental findings.
Assuntos
Estrenos/química , Esteroides/química , Estrenos/síntese química , Modelos Moleculares , Teoria Quântica , Estereoisomerismo , Esteroides/síntese química , TermodinâmicaRESUMO
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 (BAYâ 85-3934), a novel small-molecule oral HIF-PH inhibitor. Molidustat is currently being investigated in clinical phaseâ III trials as molidustat sodium for the treatment of anemia in patients with CKD.
Assuntos
Anemia/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Nefropatias/complicações , Pirazóis/farmacologia , Triazóis/farmacologia , Anemia/etiologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Camundongos , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Pirazóis/uso terapêutico , Relação Estrutura-Atividade , Triazóis/uso terapêuticoRESUMO
A series of novel beta-amino acids has been synthesized and tested for their in vitro antifungal activity against Candida albicans. A steep SAR was observed. beta-Amino acid 21 (BAY 10-8888/PLD-118) revealed the most favourable activity-tolerability profile and was selected for clinical studies as a novel antifungal for the oral treatment of yeast infections.