ALRT268 has been described previously in the scientific literature. It
is the most potent RXR-specific retinoid isolated. This increased potency
also produces more dramatic effects in vivo. For treating type II diabetes in mice here is the comparison.
Targretin and ALRT268 both reduce blood glucose levels by 40%
Targretin reduces triglycerides by 30%, ALRT268 reduces by 45%
Targretin reduces insulin levels by 20%, ALRT268 reduces by 60%
Both maintaines the anti-diabetic activity throughout the course of therapy and both were well tolerated.
Targretin was as effective as TZD while ALRT was as effective as a second generation TZD.
Both Targretin and ALRT268 produced additive effects with TZD.
The new data reinforces the Targretin and suggests that the second generation product may be more effective. The new data should raise some eybrows and produce buying pressure at the open (the Tragretin data was originally presented at Bear Stearns in September. LGND traded 1.5 million shares and the price jumped 3 points. LGND plans to start a phase II trial for type II diabetes this quarter.
Here's the earlier paper describing ALRT268 (called LG100268 in the 1995 paper. Targretin is called LGD1069):
Design and synthesis of potent retinoid X
receptor selective ligands that induce
apoptosis in leukemia cells.
Boehm MF; Zhang L; Zhi L; McClurg MR; Berger E;
Wagoner M; Mais DE; Suto CM; Davies JA; Heyman RA;
et al
Department of Retinoid Chemistry Research, Ligand Pharmaceuticals, Inc., San Diego, California
92121, USA.
J Med Chem 38: 3146-55 (1995)
Abstract
Structural modifications of the retinoid X receptor (RXR) selective compound
4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069),
which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted
in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This
paper describes the design and preparation of a series of RXR selective retinoids as well as the
biological data obtained from cotransfection and competitive binding assays which were used to
evaluate their potency and selectivity. The most potent and selective of the analogs is
6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d;
LG100268). This compound has proven useful for investigating RXR dependent biological pathways
including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our
studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent
upon activation of RXR-mediated pathways. |
