Barnett S. Pitzele

4-Fluorinated L-lysine analogs as selective i-NOS inhibitors: methodology for introducing fluorine into the lysine side chain.

In the literature, the introduction of fluorine into bioactive molecules has been known to enhance the biological activity relative to the parent molecule. Described in this article is the synthesis of 4R-fluoro-L-NIL (12) and 4,4-difluoro-L-NIL (23) as part of our iNOS program. Both 12 and 23 were found to be selective iNOS inhibitors as shown in Table 2 below. Secondarily, methodology to synthesize orthogonally protected 4-fluoro-L-lysine and 4,4-difluoro-L-lysine has been developed.

γ-alkylation of α,β-unsaturated acids : A technique of stereospecific isoprenoid homologation

Abstract This paper describes the synthesis of various isomers of farnesol by means of two different isoprenoid homologations; the γ-alkylation of 2-butynoic acid and the γ-alkylation of 3-methyl crotonic acid.

Selective heterocyclic amidine inhibitors of human inducible nitric oxide synthase

The potency and selectivity of a series of 5-hetero-2-iminohexahydroazepines were examined as inhibitors of the three human NOS isoforms. The effect of ring substitution of the 5-carbon for a heteroatom is presented. Potencies (IC(50)s) for these inhibitors are in the low micromolar range for hi-NOS with some examples exhibiting a 500x selectivity versus hec-NOS.

3-Hydroxy-4-methyl-5-pentyl-2-iminopyrrolidine: a potent and highly selective inducible nitric oxide synthase inhibitor.

(3S,4S,5R)-2-Imino-4-methyl-5-pentyl-3-pyrrolidinol hydrochloride (1) is a potent inducible nitric oxide synthase (i-NOS) inhibitor that has three times the selectivity of its parent, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine hydrochloride (2).

The N-Boc Group as an Activator for the a-Lithiation of Carbamates: Synthesis of 11-Substituted Dibenzoxazepines

A series of 11-substituted dibenzoxazepines was prepared via α-lithiation utilizing the N-Boc group as an activator. The N-Boc group directs metalation of 5 by n-BuLi to the benzylic C-11 carbon. For 6 which contains 1,3 interrelated directed metalation groups, metalation with n-BuLi occurs at both the 11- and 9- positions. The regioselectivity for the lithiation of 6 can be increased to a ratio of 97:3, by employing LDA as the base, thus providing a convenient and general route to 11-substituted 8-chloro-dibenzoxazepines. By the proper choice of the base, the regioselectivity of lithiation-substitution reactions in the pharmaceutically important heteroaromatic ring systems (5) and (6) can be controlled. The N-Boc group can be readily removed with mild acid treatment

Syntheses of new racemic NG‐(1‐iminoethyl)phosphalysine derivatives as potential inhibitors of nitric oxide synthase

The efficient syntheses of three new racemic NG-(1-iminoethyl)phosphalysine derivatives are reported where the lysine carboxylate group is systematically replaced by phosphonic acid, 4, methyl phosphinic acid, 5, and phosphinic acid, 6. These compounds were evaluated as potential inhibitors of the three isoforms of human nitric oxide synthase.