IC50 22 nM.human-EPHX2. 5ALU-HD2 is also inhibitor of 11-beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome Human HTRF in vitro potency: 21nM Murine HTRF in vitro potency:32 nM Murine in vivi (PK/PD) potency: 50nM. It has been cristallized with 11beta-HSD1 pdb:4BB5 Goldberg et al.
Title: Successful generation of structural information for fragment-based drug discovery Oster L, Tapani S, Xue Y, Kack H Ref: Drug Discov Today, 20:1104, 2015 : PubMed
Fragment-based drug discovery relies upon structural information for efficient compound progression, yet it is often challenging to generate structures with bound fragments. A summary of recent literature reveals that a wide repertoire of experimental procedures is employed to generate ligand-bound crystal structures successfully. We share in-house experience from setting up and executing fragment crystallography in a project that resulted in 55 complex structures. The ligands span five orders of magnitude in affinity and the resulting structures are made available to be of use, for example, for development of computational methods. Analysis of the results revealed that ligand properties such as potency, ligand efficiency (LE) and, to some degree, clogP influence the success of complex structure generation.
11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11beta-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described-a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.
