W. Stephen Faraci

Phosphodiesterases in the CNS: targets for drug development

The therapeutic and commercial success of phosphodiesterase 5 inhibitors such as Viagra, Levitra and Cialis has sparked renewed interest in the phosphodiesterases as drug discovery targets. Virtually all the phosphodiesterases are expressed in the CNS, making this gene family a particularly attractive source of new targets for the treatment of psychiatric and neurodegenerative disorders. Significantly, all neurons express multiple phosphodiesterases, which differ in cyclic nucleotide specificity, affinity, regulatory control and subcellular compartmentalization. Therefore, phosphodiesterase inhibition represents a mechanism through which it could be possible to precisely modulate neuronal activity. In this article, we review the current state of the art in the burgeoning field of phosphodiesterase pharmacology in the CNS.

CP-99,711: a non-peptide glucagon receptor antagonist

Abstract CP-99,711, identified in a screening program, displaces [125I]-glucagon from its rat liver receptor. We describe here the synthesis of this compound and its characterization as a functional glucagon receptor antagonist.

Inhibition of Helicobacter pylori Urease by Phenyl Phosphorodiamidates: Mechanism of Action

Helicobacter pylori urease is a nickel-containing enzyme that hydrolyzes urea to bicarbonate and ammonia. Andrews et al. (J. Am. Chem. Soc. 1986, 108, 7124) have shown that amides and esters of phosphoric acid are slow, tight-binding inhibitors of urease isolated from jack bean. We show that 4-substituted phenyl phosphorodiamidates (4-R-PhOP(=O)(NH2)2) are slow-binding inhibitors of H. pylori urease with no evidence of kinetic saturation. Their second-order rates of inhibition ki are strongly correlated with phenol pKa (e.g. R = NO2, ki = 2.5 x 10(5) M-1s-1; R = OMe, ki = 1.2 x 10(4) M-1s-1). The Bronsted beta for inhibition is 0.4, similar to that of model system SN2(P) reactions. Based on these observations, we suggest that urease inhibition is covalent but reversible, involving a common phosphoacyl enzyme intermediate.

Synthesis, sar and pharmacology of CP-293,019 : A potent, selective dopamine D4 receptor antagonist

A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.

A new class of selective and potent inhibitors of neuronal nitric oxide synthase.

The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.

The discovery of potent and selective dopamine D4 receptor antagonists

The identification of a novel dopamine receptor subtype, referred to as the D4 receptor, which binds the atypical antipsychotic drug clozapine with high potency, has led to the initiation of a drug discovery program that aims to find novel inhibitors of this receptor subtype. A selective screening strategy was utilized, in which 4500 compounds chosen on the basis of structural similarities to known biogenic amine receptor antagonists were tested against both the D4 and D2 dopamine receptor subtypes. A potent D4-selective compound was discovered.

Inhibition of human leukocyte elastase (HLE) by novel bicyclic β-lactams

Abstract Novel 3,2,0 bicyclic β-lactam sulfenamides and selected carbon isosteres are inhibitors of human leukocyte elastase. The comparative biological activity and hydrolytic stability of these compounds are described.

Novel in vitro and in vivo inhibitors of prolyl endopeptidase

Abstract Inhibition of prolyl endopeptidase by Z-cyclohexyl prolinal and Z-indolinyl prolinal occurs with slow, tight binding inhibition and K i values of 2 – 3 nM. In vivo enzyme inhibition is also observed with a half time for recovery of enzyme activity of 3 – 4 h. Inhibition of prolyl endopeptidase by Z-cyclohexyl prolinal and Z-indolinyl prolinal occurs with slow, tight binding inhibition and K i values of 2 – 3 nM. In vivo enzyme inhibition is also observed with a half time for recovery of enzyme activity of 3 – 4 h.