Z944 R1=F, R2=Cl

http://courses.washington.edu/phcol512/data/Tringham.pdf

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Research Article

EPILEPSY

T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures

• Elizabeth Tringham, et AL

Sci Transl Med 15 February 2012 4:121ra19. DOI:10.1126/scitranslmed.3003120

…T-type calcium channel blockers, termed Z941 and Z944, were identified

http://stm.sciencemag.org/search?journal_search_keyword_go.y=8&submit=yes&fulltext=z944&andorexacttitleabs=and&andorexactfulltext=and&where=fulltext&journal_search_keyword_go.x=10&hopnum=1

Key Patent Provides Broad Coverage for Z944 through April 2029

CAMBRIDGE, Mass.Feb 20, 2013 – Zalicus Inc. , a biopharmaceutical company that discovers and develops novel treatments for patients suffering from pain, today announced that it has been granted a patent by the U.S. Patent and Trademark office (USPTO) covering its product candidate Z944. United States patent number 8,377,968 entitled “N-Piperidinyl Acetamide Derivatives as Calcium Channel Blockers” provides broad coverage for Z944 including compositions of matter and certain therapeutic methods of use through April 2029. Z944 is a novel, oral, T-type calcium channel blocker which has demonstrated efficacy in a number of preclinical inflammatory pain models and other disease models. Z944 completed Phase 1 single and multiple ascending dose clinical studies in late 2012 and the Company plans to continue further clinical development with Z944 during 2013.

“This key patent provides the foundation of a solid and enforceable intellectual property estate for Z944, with issued claims through April 2029,” commented Mark H.N. Corrigan, MD, President and CEO of Zalicus. “Based on our preclinical and early-stage clinical work, we are excited to further explore the potential of Z944 as a novel, oral, non-opioid pain treatment.”

Absence seizures — which are a common type of seizure in children with genetic generalized epilepsy — could now be treated by a potential new class of drugs with enhanced selectivity and efficacy over the drugs that are currently used in the clinic.

The molecular mechanisms underlying absence seizures are unclear; nevertheless, current literature indicates that the low-voltage-activated Cav3.1 and Cav3.2 T-type calcium channels have a crucial role. T-type calcium channels are also thought to be the site of action of the first-line drug ethosuximide; however, as it is nonspecific, ethosuximide causes side effects such as drowsiness, and not all patients respond to treatment. Therefore, the authors sought to identify a more specific and potent T-type calcium channel blocker.

A rational drug design approach produced two candidates — Z941 and Z944 — that had suitable properties for further development. They both had nanomolar affinities for Cav3.2 channels and significantly improved potencies compared to ethosuximide and valproate (another drug used for treating absence seizures). Importantly, Z944 has a higher affinity for the inactivated state of T-type channels (the state that is predominant during seizure activity) than for the closed state, and a higher affinity for neuronal T-type channels than for the cardiovascular-related channels.