The identification of AF38469: an orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin

Tenna Juul Schrøder; Søren Christensen; Samsa Lindberg; Morten Langgård; Laurent David; Philip J Maltas; Jørgen Eskildsen; Jan Jacobsen; Lena Tagmose; Klaus Bæk Simonsen; Lars Christian Biilmann Rønn; Inge E M de Jong; Ibrahim J Malik; Jens-Jakob Karlsson; Christoffer Bundgaard; Jan Egebjerg; Jeffrey B Stavenhagen; Dorthe Strandbygård; Søren Thirup; Jacob Lauwring Andersen; Srinivas Uppalanchi; Sridhar Pervaram; Shiva Prasad Kasturi; Pradheep Eradi; Durga Rao Sakumudi; Stephen P Watson

doi:10.1016/j.bmcl.2013.11.046

The identification of AF38469: an orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin

Bioorg Med Chem Lett. 2014 Jan 1;24(1):177-80. doi: 10.1016/j.bmcl.2013.11.046. Epub 2013 Nov 27.

Authors

Tenna Juul Schrøder¹, Søren Christensen¹, Samsa Lindberg¹, Morten Langgård¹, Laurent David¹, Philip J Maltas¹, Jørgen Eskildsen¹, Jan Jacobsen¹, Lena Tagmose¹, Klaus Bæk Simonsen¹, Lars Christian Biilmann Rønn¹, Inge E M de Jong¹, Ibrahim J Malik¹, Jens-Jakob Karlsson¹, Christoffer Bundgaard¹, Jan Egebjerg¹, Jeffrey B Stavenhagen¹, Dorthe Strandbygård², Søren Thirup², Jacob Lauwring Andersen², Srinivas Uppalanchi³, Sridhar Pervaram³, Shiva Prasad Kasturi³, Pradheep Eradi³, Durga Rao Sakumudi³, Stephen P Watson⁴

Affiliations

¹ Neuroscience Drug Discovery, H. Lundbeck A/S, Copenhagen, Denmark.
² The Lundbeck Foundation Research Centre MIND, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, Aarhus C 8000, Denmark.
³ Medicinal Chemistry, GVK BioScience, Hyderabad, India.
⁴ Neuroscience Drug Discovery, H. Lundbeck A/S, Copenhagen, Denmark. Electronic address: [email protected].

PMID: 24355129
DOI: 10.1016/j.bmcl.2013.11.046

Abstract

The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.

Keywords: AF38469; AF40431; Neurotensin; Protein-inhibitor complex; Sortilin; Sortilin crystal structure; Sorting receptor; VPS10P.

MeSH terms

Adaptor Proteins, Vesicular Transport / antagonists & inhibitors*
Administration, Oral
Animals
Biological Availability
Crystallography, X-Ray
Dose-Response Relationship, Drug
High-Throughput Screening Assays
Hydrocarbons, Fluorinated / chemical synthesis
Hydrocarbons, Fluorinated / chemistry
Hydrocarbons, Fluorinated / pharmacology*
Models, Molecular
Molecular Structure
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Rats
Structure-Activity Relationship

Substances

AF38469
Adaptor Proteins, Vesicular Transport
Hydrocarbons, Fluorinated
Pyridines
sortilin