Format

Send to

Choose Destination
Bioorg Med Chem Lett. 2015 Sep 15;25(18):4005-10. doi: 10.1016/j.bmcl.2015.07.009. Epub 2015 Jul 10.

Design, synthesis and biological characterization of selective LIMK inhibitors.

Author information

1
Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium. Electronic address: sandro.boland@amakem.com.
2
Amakem Therapeutics N.V., Agoralaan Abis, 3590 Diepenbeek, Belgium.
3
Laboratory of Ophthalmology, KU Leuven, 3000 Leuven, Belgium.

Abstract

Inhibitors of LIM kinases are considered of interest for several indications, including elevated intraocular pressure (IOP), cancer, or infection by HIV-1. LX-7101 (Lexicon Pharmaceuticals) was advanced to Phase-I clinical trials as an IOP-lowering agent for treatment of glaucoma. We here discuss the design, synthesis and evaluation of LIMK inhibitors based on a pyrrolopyrimidine scaffold, which represent close analogs of LX-7101. Exploration of structure-activity relationships revealed that many of such compounds, including LX-7101, cause potent inhibition of LIMK1 and LIMK2, and also ROCK2 and PKA. Molecular variations around the various structural elements of LX-7101 were attempted. Substitution on position 6 of the pyrrolopyrimidine scaffold led to the identification of LX-7101 analogs displaying good selectivity versus ROCK, PKA and Akt.

KEYWORDS:

Kinase inhibitor; LIMK; LX-7101; ROCK; SAR

PMID:
26233434
DOI:
10.1016/j.bmcl.2015.07.009
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center