Michael H. Parker

The role of sulfamide derivatives in medicinal chemistry: a patent review (2006-2008).

Background: The sulfamide (R2NSO2NR2) functionality is an acceptable functional group in medicinal chemistry when incorporated into putative small-molecule therapeutics, as it has the potential to form several electrostatic interactions with protein and other targets. The clinically-useful broad spectrum antibiotic doripenem contains a mono-substituted sulfamide. The sulfamide functional group is often found to substitute for sulfonamide, sulfamate or urea functionality. Objective/method: During the period of 2006 – 2008, there were nine published patents in which all or most reported compounds contained the sulfamide functional group. There are also patents in which the structures disclosed contain a cyclic sulfamide functional group. Further, there are patents published during this timeframe that contain only a few sulfamide-containing examples, typically as a bioisosteric replacement for a sulfonamide moiety. In this review, we focus on those published patents in which most compounds disclosed are sulfamides and only briefly highlight examples in which sulfamides are included among a large list of other suitable functionalities. Conclusion: While the sulfamide functionality is still fairly under-represented in medicinal chemistry, it is a valuable and versatile group that will gain increasing acceptance and favor in the future.

Synthesis of (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene: An inhibitor of β-Amyloid1-42 aggregation

A concise synthesis of the beta-amyloid(1-42 )aggregation inhibitor (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(-)-2] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene into amine. Enantiomeric resolution was achieved by recrystallization of amine as the dibenzoyl-D-tartaric acid salt. Hydroquinone is a potent inhibitor of the fibrillar aggregation of beta-amyloid as determined in two different assay systems.

Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.

We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimers disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).

The Preparation and Human Muscarinic Receptor Profiling of Oxybutynin and N-Desethyloxybutynin Enantiomers

Oxybutynin (1) is a non-selective muscarinic receptor antagonist that is used clinically for the treatment of urinary incontinence. The major metabolite of oxybutynin in humans is desethyloxybutynin (2). We have prepared the enantiomers of 1 and 2 and evaluated their ability to displace N-CT(3)-scopolamine chloride ((3)H-NMS) binding on human cloned muscarinic m1-5 receptors. Compounds 1 and 2 potently displaced (3)H-NMS binding at m1, m3 and m4 receptors, but were less potent at the m2 and m5 subtypes. However, metabolite 2 was more potent than the parent compound 1 in the binding assay. In general the R enantiomers were more potent than their respective S enantiomers. Therefore, we suggest that the cholinergic side effects associated with 2 may be due to its greater apparent potency with m1 and m3 receptors, especially of its R-enantiomer, when compared with parent drug 1.

Synthesis of bis‐Phenylalanine, A Novel Eight‐Membered Cyclic Dipeptide

Abstract Cyclic eight‐membered ring lactams have been prepared which are formally analogs of Phe‐Ala or Ala‐Phe dipeptides joined together on their side chains. These are termed bis‐phenylalanines because they are phenylalanine with respect to both of the residues in which the phenyl ring is shared between the two. The key synthetic step was the Negishi coupling of Boc‐β‐I‐Ala methyl ester with a suitably protected 2′‐I phenylalanine.