ABSTRACT
The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and associated glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aqueous stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aqueous stable compounds, and addition of solubilizing groups resulted in a set of compounds with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clinical candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clinical trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.
ABSTRACT
The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocular pressure to baseline levels. The compounds also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and associated glaucoma.
Subject(s)
Antihypertensive Agents/chemical synthesis , Lim Kinases/antagonists & inhibitors , Ocular Hypertension/drug therapy , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Administration, Topical , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Glaucoma/drug therapy , Glaucoma/physiopathology , Guanidines/chemical synthesis , Guanidines/chemistry , Guanidines/pharmacology , In Vitro Techniques , Intraocular Pressure/drug effects , Mice , Nitriles/chemical synthesis , Nitriles/chemistry , Nitriles/pharmacology , Ocular Hypertension/chemically induced , Ocular Hypertension/physiopathology , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , Swine , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacologyABSTRACT
The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.
