Niels Skjaerbaek

Exploring the potential for subtype-selective muscarinic agonists in glaucoma

Pilocarpine has been used to lower intraocular pressure (IOP) in glaucoma patients for more than 100 years. Since the identification of five muscarinic receptor subtypes, there has been an interest in separating the IOP-lowering effects from the ocular side effects of pupil constriction and lens accommodation. However, all these actions seem to be mediated by the M3 receptor. A novel muscarinic receptor agonist, AGN 199170, that has no activity on the M3 subtype was compared to pilocarpine in a monkey glaucoma model. This compound lowered IOP suggesting that muscarinic agonists targeted at muscarinic receptors other than the M3 subtype may be able to selectively lower IOP.

Excitatory amino acids. Synthesis of (RS)-2-amino-3-(5-cyclopropyl-3-hydroxyisoxazol-4-yl)propionic acid, a new potent and specific AMPA receptor agonist

The synthesis of (RS)-2-amino-3-(5-cyclopropyl-3-hydroxyisoxazol-4-yl)propionic acid 6, an analogue of the AMPA receptor agonist (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid, AMPA, 3 is described. Compound 6 has been studied in vitro in radioligand binding and electrophysiological test systems and shown to be a specific AMPA receptor agonist equipotent with AMPA. The synthesis of 6 was based on 5-cyclopropyl-3-hydroxyisoxazole 8, which was converted into the intermediate 4-bromomethyl-5-(3-bromopropyl)-2-methoxymethyl-2,3-dihydroisoxazol-3-one 9 by opening of the cyclopropane ring. Based on 1H and 13C NMR data, this conversion has been shown to proceed stepwise, the progression of the different steps being dependent on the concentration of the hydrobromic acid medium, reaction time, and temperature. An acetamidomalonate group has been regiospecifically substituted for the allylic bromine atom of 9 to give 10, and treatment of 10 with sodium hydride gave compound 11 containing a cyclopropyl group, reformed by cyclization of the 3-bromopropyl substituent of 10. Compound 11 has been fully deprotected by treatment with aqueous trifluoroacetic acid to give 6.

Regioselective acylation of 1-hydroxypyrazoles via metalated intermediates

A range of C-4 and C-5 acylated 1-benzyloxypyrazoles (7a–e) and (4) have been prepared via Pd(0) catalysed cross-coupling between acid chlorides and 1-benzyloxy-4-(tributylstannyl)pyrazole (8) or 1-benzyloxypyrazol-5-ylzinc chloride. 3-Acylated 2-(4-methoxybenzyl)-2H-pyrazole 1-oxides (15a–f) were formed by reaction between the 3-magnesiated 2H-pyrazole 1-oxide (14) and acid chlorides. The benzyl group of 4 and 7a and the 4-methoxybenzyl (PMB) group of 15a were removed by treatment with conc. HCl or TFA in the presence of water, furnishing the corresponding C-acylated 1-hydroxypyrazoles.