Reinhardt Bernhard Baudy

Prodrugs of Perzinfotel with Improved Oral Bioavailability

Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

Advances toward New Antidepressants with Dual Serotonin Transporter and 5-HT1A Receptor Affinity within a Class of 3-Aminochroman Derivatives. Part 2

Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.

Synthesis of the Four 3‐Aminotricyclo [2.2.1.0(2,6)] Heptane‐1,3‐Dicarboxylic Acid Isomers

Abstract A process to prepare the four stereoisomers of the tricyclic 3‐aminotricyclo[2.2.1.0(2,6)] heptane‐1,3‐dicarboxylic acid, a potent selective inhibitor of the EAAT2 transporter, is described.

Agents for the treatment of neurodegenerative diseases: July - December 1997

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. Selected patent activities are described and summarised below for the period of July through December 1997. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

Patent Update Central & Peripheral Nervous Systems: Agents for the treatment of neurodegenerative diseases: January - June 1996

This patent update relates to agents for the treatment of neurodegenerative diseases, for both the peripheral and central nervous systems. Selected patent activities are described and summarised below for the period of January through June 1996. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

Central & Peripheral Nervous System: Agents for the treatment of neurodegenerative diseases: part 3

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. The patenting activity is described and summarised for the period between July and December 1995. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

Agents for the treatment of neurodegenerative diseases: January - June 1998

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. Selected patent activities are described and summarised below for the period of January through June 1998. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents that either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

Patent Update Central & Peripheral Nervous Systems: Agents for the treatment of neurodegenerative diseases: Part 6

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. The patenting activity is described and summarised for the period between July and December 1995. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.