Peptidase-4 inhibitors

Table 4. Neural Endopeptidase (Atrial Peptidase) Inhibitors...

Table 1 lists peptidases that are known orpotential drug targqs. In nearly all cases the drag will be a synthetic peptidase inhibitor [4]. 

Summation The overall response is the arithmetic sum of the contribution brought by each receptor (e.g., NKX and NK2). Capsaicin-induced contraction of rat isolated urinary bladder, electrical field stimulation (EFS)-induced nonadrenergic, noncholinergic contraction of the isolated guinea pig bronchus or renal pelvis when SP metabolism is blocked by peptidase inhibitors are all examples of summation. Both NK and NK2r antagonists are required to abolish such kind of response, but each antagonist substantially reduces the response... 

Faraj et al. [28] studied the effects of different concentrations of leucine enkephalin, peptidase inhibitors, and sodium glycocholate (GC) on the stability and absorption of leucine enkephalin in nasal cavities of rats. Based on the study, the rate and extent of formation of des-tyrosine leucine enkephalin... 

Serine protease inhibitor that inhibits trypsin, chymotrypsin, kallikrein, and plasmin Binding is reversible, with most aprotinin-protease complexes dissociating at pH>10or <3 Peptidase inhibitor... 

Dash C, Kulkarni A, Dunn B, Rao M. 2003. Aspartic peptidase inhibitors implications in drug development. Grit Rev Biochem Mol Biol 38 89-119. 

Drucker DJ, Nauck M. The incretin system glucagonslike peptide-1 agonist and dipeptidyl peptidase inhibitors in type 2 diabetes. Lancet 2006 368 1696-705. 

This method is compatible with many functional groups and shows considerable selectivity. Phosphonic acid esters may be cleaved in the presence of carboxylic acid esters, and phosphonate methyl esters are cleaved approximately 25 times faster than the isopropyl esters. For example, the phosphonate methyl ester of the hexapeptide analogue 78 was cleaved with TMSBr to give the aspartic peptidase inhibitor 79 in 64% yield (Scheme 28). 66 ... 

Support-bound, enantiomerically pure alcohols can be converted into phosphonates by Mitsunobu esterification, which results in complete inversion at the stereo-genic center. This strategy has been used to prepare peptidyl phosphonates on solid phase. These are interesting transition-state analogs with potential utility as peptidase inhibitors (Figure 11.3 [12,13]) or tyrosine phosphatase inhibitors [14]. Serine or threonine derivatives can be converted into phosphonates by direct phosphonylation with an activated monoalkyl phosphonate [15] or by treatment with phosphonamidites RP(OR)NR2 in the presence of tetrazole followed by oxidation [16]. 

Atrial Natriuretic Peptide Potentiator Diuretics. Neural endopeptidase inhibitors or atrial peptidase inhibitors are compounds that inhibit the enzyme (hat degrades ANP. resulting in higher plasma concemratioas, and longer duration of action, of ANP. The diuretic effects of this class... 

Fig. 1.7 Chemical structures of NAAG peptidase inhibitors. ZJ-43, a urea-based NAAG analog, Ki 0.8 nM (a) PMPA (2-(phosphonomethyl)pentanedioic acid), Ki 280 pM (b) PMSA (2-(phosphonomethyl)succinic acid), Ki 2.6 /itM (c) and pyrazole (d)...

It may be possible to achieve significant penetration enhancement by using a combination of other penetration enhancers and peptidase inhibitors. 

To improve the absorption of peptides and proteins, the employment of different enzymatic inhibitors has been suggested. For example, some authors have demonstrated the usefulness of inhibitors of both exo- and endopeptidases to promote calcitonin absorption across rat vaginal mucosa [93]. A direct relationship was found between the effect of peptidase inhibitors of in vitro degradation constant of calcitonin in vaginal mucosa homogenates and in vivo promotion of drug absorption, indicated by the decrease in plasma calcium levels after calcitonin administration in rats. The peptidase inhibitors tested were pepstatin, bestatin, and leupeptin. 

Plasma prepared with strong chelators such as ethylene diamine tetraacetic acid (EDTA) may act as peptidase inhibitors for metalloproteases and peptidases using divalent cations as cofactors (28). 

The transport-enhancing effect of Zot was shown to be reversible and nontoxic (Fasano et al. 1991 Cox et al. 2002). More recently a smaller fragment of Zot in the size of 12 kDa referred to as /1G was identified (Di Pierro et al. 2001). AG displayed significant potential as permeation enhancer. In vitro studies showed that it is capable of significantly increasing the apparent permeability coefficients for a wide variety of drugs across Caco-2 monolayer (Salama et al. 2003, 2004). In the presence of peptidase inhibitors AG improved the bioavailability of mannitol, inulin and PEG 4000 after intraduodenal administration to rats (Salama et al. 2003, 2004). In another in vivo study the oral bioavailability of cyclosporin A was increased up to 50-fold due to the co-administration of AG when metabolic protection was provided (Salama et al. 2005). Results of this study are illustrated in Fig. 5.2. 

Schwartz et al. 45 b) have recently discussed numerous pharmacological aspects of enkephalin inhibitors such as the analgesic effect, drug design, model predictions about the active center, and the protection of endogenous neuropeptides by peptidase inhibitors. 

Summary of antimicrobial agents affecting cell wall synthesis [Note Cilastatin is not an antibiotic but a peptidase inhibitor that protects imipenem from degradation.]... 

MODIFICATIONS OF THE METHOD It can be appropriate to coincubate the compound of interest in the presence of inhibitors of serum esterases. Used is sodium fluoride, physostigmin or ecothiophate iodide (Chien 1990 Quon et al. 1993). In case of carboxy- or aminopeptidase cleavage of peptides specific peptidase inhibitors like amastatin, bestatin, phenylmethylsulphonylfluoride, 1,10-phenanthroline or ethylenediamine tetra acetic acid (EDTA) are useful (Lee 1995). 

Zhou J, Neale JH, Pomper MG, Kozikowski AP. 2005. NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nat Rev 4 1015-1026. 

Merck process research group developed a short and efficient synthesis of 3-(2,2,2-trifluoroethyl)-hexahydro-2//-l,4-diazepin-2-one 85 as part of an ongoing research program to identify peptidase inhibitors <07S2779>. 

Adams, S., Miller, G. T., Jesson, M. I., Watanabe,T, Jones, B., Wallner, B. P. (2004). PT-100, a small molecule dipepfi-dyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 64, 5471-5480. 

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