Malcolm R. Bell

C-ATTACHED AMINOALKYLINDOLES : POTENT CANNABINOID MIMETICS

Abstract Aminoalkylindoles (AAIs) with potent cannabinoid agonist activity have been synthesized where the aminoalkyl chain is attached to the indole ring via a carbon atom of the cyclic amine.

A benzisothiazolone class of potent, selective mechanism-based inhibitors of human leukocyte elastase

Abstract A new type of mechanism-based inhibitor of human leukocyte elastase (HLE) is described that are designed to inhibit HLE by a suicide route to form an inhibitor-enzyme complex by cross linking the enzyme active site. A mechanism of HLE inhibition is proposed and was used to design analogues with improved potency. The structure-activity relationships described in this paper are consistent with the proposed mechanism of HLE inhibition, and led to WIN 62785 ( 12 ), the most potent compound in this series with a K i * = 0.3 nM.

Morpholinoalkylindenes as antinociceptive agents: Novel cannabinoid receptor agonists

Abstract Indence analogs of pravadoline exhibited antinociceptive activity in several animal models. The inhibition of prostaglandin (PG) synthesis in mouse brain microsomes was diminished in these pravadoline analogs, but they were potent in inhibiting electrically stimulated contractions in the mouse vas deferens (MVD) preparations. Binding studies with ligand WIN 55212-2 have aided to demonstrate that the morpholinoalkyl-indene binding site is functionally equivalent with cannabinoid binding site. The antinociceptive activity of the indene derivatives appears to be mediated by increased affinity for the cannabinoid receptor.

The design of potent and stable benzisothiazolone inhibitors of human leukocyte elastase

Abstract The lead compound for this SAR study, benzisothiazolone 1a, was a 15 nM inhibitor of HLE, but was unstable in human blood ( t 1 2 min). The introduction of lipophilic substituents at the R4-position such as ethyl or isopropyl and modulation of the electrophilicity of the benzisothiazolone carbonyl led to the identification of a potent ( K i ∗ =0.27 nM) and blood stable ( t 1 2 =260 min) inhibitor 2e, WIN 63395.

Novel method for the preparation of monofluoroacetyl and difluoroacetylfuran derivatives

Abstract Monofluoroacetyl and difluoroacetylsteroidal furans were prepared by selective reductive dehalogenation of chlorofluoro and chlorodifluoroacetyl intermediates with sodium formaldehyde sulfoxylate.

Inhibitors of human leukocyte elastase. 2.1 synthesis and sar of benzisothiazolinylmethyl aryl ethers

Abstract A series of 4-isopropyl benzisothiazolinylmethyl aryl ethers were prepared and evaluated as inhibitors of human leukocyte elastase (HLE). Among the phenols attached as leaving groups onto N-methyl of the 4-isopropyl benzisothiazolone nucleus, the sulfonamido phenol 26 was found to be the best. Compound 7i with K i ∗ = 0.8 nM was the most potent inhibitor in this series.

Inhibitors of human leukocyte elastase. 3.1 inhibition by tetrahydrobenzisothiazolinylmethyl aryl carboxylates

Abstract Potent mechanism based inhibition of human leukocyte elastase (HLE) by tetrahydrobenzisothiazolones ( 2 ) is described. Structure activity relationships studies led to the identification of WIN 62816 ( 2c ), the most potent inhibitor in this series with a K i ∗ = 0.7 nM.

An unprecendented reaction of diethylaminosulfur trifluoride with furanones

Reaction of diethylaminosulfur trifluoride (DAST) with furanones did not provide the expected gem-difluoro compounds instead the methylene hydrogens of furanones were replaced by a fluorine and sulfinyl group

Dianion metallation reactions of N,N-dimethylvanillylamine and N,N-dimethylisovanillylamine

The utility of dianion chemistry in the synthesis of polyfunctional aromatics is demonstrated by the direct lithiation of the vanillylamine 1 and by the metal-halogen exchange reaction of the bromo isovanillylamines 9 and 10.

Synthesis and androgen receptor affisity of steroidal methylsulfonylforans and a menthylsulfonylthiophene

Abstract Syntheses of the unsubstituted steroidal [3,2-b]furan ( 3a ), thiophene ( 3b ) and [2,3-b]furan ( 24 ) are described. Lithiation of the THP ethers 18a and 18b followed by the reaction with methyl disulfide and deprotection gave the 5′-methylsulfide derivatives 19a and 19b . Oxidation of the sulfides and ethynylation provided the compounds 2a and 2b . Swern oxidation of the [2,3-b]furan 24 with DMSO/TFAA/diisopropylethylamine resulted in oxidation to the 17-ketone and introduction of a 5′-methylthio group to give 25 . Ethynylation at C-17 followed by oxidation of the sulfide group provided the product 27 . 5′-Methylsulfonyl[3,2-b]furanosteroid 2a bound to the rat ventral prostate androgen receptor. However, the corresponding thiophene 2b and the [2,3-b]furan 27 lacked affinity for the receptor.