Mark A. Russell

Pharmacological Characterization of SC-57461A (3-(Methyl(3- (4-(phenylmethyl)phenoxy)propyl)amino)propanoic Acid HCl), a Potent and Selective Inhibitor of Leukotriene A 4 Hydrolase I: In Vitro Studies

Leukotriene (LT) B(4) is an inflammatory mediator that has been implicated in the pathogenesis of various diseases, including inflammatory bowel disease and psoriasis. As the rate-limiting step for LTB(4) production, LTA(4) hydrolase represents an attractive target for therapeutic agents that interfere with LTB(4) production. In the present study we evaluated a chemically novel compound designated SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) as an inhibitor of LTA(4) hydrolase. Pharmacological comparisons are made to its free acid SC-57461. SC-57461A is a potent competitive inhibitor of recombinant human LTA(4) hydrolase when either LTA(4) (IC(50) = 2.5 nM, K(i) = 23 nM) or peptide substrates (IC(50) = 27 nM) are used. In human whole blood, the IC(50) for calcium ionophore-induced LTB(4) production was 49 nM, indicative of good cell penetration. Whole blood production of the cyclooxygenase metabolite thromboxane B(2) was not affected. SC-57461A was also active in several other species, including mouse, rat, dog, and rhesus monkey. The data indicate that SC-57461A is a potent and selective inhibitor of LTA(4) hydrolase.

A new class of orally active glycol renin inhibitors containing phenyllactic acid at P3.

We prepared a new series of renin inhibitors based on dipeptide glycols, replacing the P4-P3 subsites with an O-(N-morpholinocarbonyl)-3-L-phenyllactic acid residue. This modification proved bioisosteric with Boc-L-phenylalanine, giving rise to highly potent human renin inhibitors (1-5 nM), e.g., SC-46944 (IC50 = 5 nM). Moreover, this change produced compounds that are orally efficacious in reducing plasma renin activity in salt-depleted marmosets.

Stereoselective Δ4-pipecolic acid synthesis via alkylation of a vinyl N-Boc-iminium ion derived from Baikiain

Stereoselective functionalization of Boc-(±)-Baikian was demonstrated via seleno- and iodolactonization to afford lactones 5. These were converted to enecarbamate 7, which undergoes regio- and stereoselective alkylation at C-6 upon treatment with organoaluminum reagents.

Phenylthionitromethane: a versatile reagent for the conversion of aldehydes into α-substituted S-phenyl thioesters

Acetaldehyde and isobutyraldehyde, RCHO, reacted with phenylthionitromethane (KOH, MeOH) followed by methanesulphonyl chloride (Et3N, CH2Cl2) to give the alkenes, RCHC(SPh)NO2; these reacted with the nuclophiles [Nu = NaOMe, NaOPri potassium Phthalimide, CH2FCONHK, p-MeC6H4SO2Na.2H2O, or KCH(CO2Me)2] in N,N-dimethylformamide (DMF), MeOH, or PriOH at –30°C to give, on subsequent ozonolysis (MeOH–DMF; –78°C) the title thioesters, [RCH(Nu)COSPh](46–79%).

Novel anionic reagents for the stereoselective synthesis of γ-hydroxy-α-amino-acids. An X-ray crystallographic study of 2R(S)-benzoylamino-N-t-butyl-4R(S)-hydroxy-4-(4-methoxyphenyl)-3R(S)-methylbutanamide

The isoxazoline trans-Ar[graphic omitted])CONHBut and oxime threo-ArCH(OH)CH(Me)C(NOSiMe2-But)CONHBut, prepared respectively from 4-methoxybenzaldehyde (ArCHO) and the anions MeCHC-(–)C(NBut) and MeCHC(–OSiMe2But)C(NBut), were reduced stereoselectively (25:1) and benzoylated to produce the title amide which was characterized by an X-ray analysis.