Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives

Journal of Medicinal Chemistry
B E MaryanoffJ L Vaught

Abstract

We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that was discovered in our laboratories. Systematic structural modification of the parent compound was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacological importance of several molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4, 5-fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the hyd...Continue Reading

References

Dec 1, 1990·International Journal of Biological Macromolecules·J VidgrenN P Walker
Jul 15, 1990·Carbohydrate Research·K H AamlidA C Richardson
Sep 1, 1989·Journal of Medicinal Chemistry·A B ReitzB E Maryanoff
Sep 1, 1988·Trends in Biochemical Sciences·R T Fernley
Mar 11, 1994·European Journal of Pharmacology·J NakamuraM Sasa
Jan 1, 1995·Epilepsia·B F Bourgeois
Jun 1, 1996·Epilepsy Research·A Wauquier, S Zhou
Apr 1, 1997·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·E Perucca
Jan 28, 1998·Clinical Therapeutics·W E Rosenfeld
Aug 1, 1997·Expert Opinion on Investigational Drugs·E Ben-Menachem

❮ Previous
Next ❯

Citations

Jun 19, 2004·Archives of Pharmacal Research·Atef Abdel-Monem Abdel-Hafez
May 18, 2004·Experimental Neurology·Carmen GlierChrysanthy Ikonomidou
Mar 6, 2003·Bioorganic & Medicinal Chemistry Letters·Nigel VickerBarry V L Potter
Dec 18, 2013·Chemical Reviews·William Spillane, Jean-Baptiste Malaubier
Jan 23, 2002·The Biochemical Journal·Rosario RecachaDebasish Chattopadhyay
Apr 17, 2001·Neuroreport·V L Smith-SwintoskyC R Plata-Salaman
Sep 3, 2011·Epilepsia·Adel A H MahmoudMohamad Al Tannir
Aug 8, 2014·Archives of Physiology and Biochemistry·Emine Rabia KoçNahit Gencer
Mar 27, 2010·The American Journal of Drug and Alcohol Abuse·Clifford M KnappDomenic A Ciraulo
Jan 8, 2015·Seizure : the Journal of the British Epilepsy Association·Eunice S M Yuen, Iñaki F Trocóniz
May 8, 2007·Pharmacology, Biochemistry, and Behavior·Clifford M KnappConan Kornetsky
Dec 24, 2003·British Journal of Pharmacology·Emilio Russo, Andrew Constanti
May 17, 2008·CNS Neuroscience & Therapeutics·Richard P Shank, Bruce E Maryanoff
Mar 22, 2013·Expert Opinion on Therapeutic Patents·Mayank AggarwalRobert McKenna
Oct 5, 2017·European Biophysics Journal : EBJ·Aurelija MickevičiūtėDaumantas Matulis
Oct 13, 2004·Medicinal Research Reviews·Jean-Yves WinumClaudiu T Supuran
Dec 14, 2006·Organic & Biomolecular Chemistry·Carol C Ruddle, Timothy P Smyth
Nov 27, 2014·Journal of Clinical Psychopharmacology·Clifford M KnappCourtney Richambault
Dec 1, 2000·The Annals of Pharmacotherapy·C J TeterC M Gibbs
Aug 17, 2016·Angewandte Chemie·Gergely L TolnaiBerit Olofsson
Sep 3, 2019·ChemMedChem·Michał AbramKrzysztof Kamiński
Sep 18, 2001·The Journal of Organic Chemistry·W J SpillaneA B O'Byrne
May 15, 2002·Journal of Combinatorial Chemistry·Elaine B KruegerArmen M Boldi
Nov 28, 2006·Journal of Chemical Information and Modeling·Alexander WeberGerhard Klebe
Apr 10, 2003·Chemical Reviews·Michał Fedoryński
Jun 24, 2004·Bioorganic & Medicinal Chemistry·Silvina M TassoGuillermina L Estiú
Jun 13, 2021·The Journal of Clinical Endocrinology and Metabolism·Alexandre Caron, Natalie Jane Michael
Jan 8, 2003·The Journal of Organic Chemistry·Serge BeaudoinJames F Burns
Aug 30, 2017·Journal of Medicinal Chemistry·Tanaji T Talele

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.