Potent activity

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Indeca.inide. Indecainide hydrochloride is a po active antiarrhythmic agent that received PDA approval in 1989, but it has not been marketed as of this writing. Chemically, it is 9-[3-(isopropylamino)propyl]fiuorine-9-carboxamide [74517-78-5]. The dmg has potent activity against premature ventricular complexes (PVCs) and ventricular tachycardias. Indecainide has no effect on sinus node function, atrial or ventricular effective refractory periods (32,33). 

FIGURE 2.7 Production of second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) through activation of the enzyme phospholipase C. This enzyme is activated by the a- subunit of Gq-protein and also by Py subunits of Gj-protein. IP3 stimulates the release of Ca2+ from intracellular stores while DAG is a potent activator of protein kinase C. 

Condensation of 594 with alloxan followed by methylation of the presumably formed purino[7,8-g]-6-azapteridine gave 597. Treatment of the latter with alkylamines afforded (87CPB4031) [1,2,4]triazino[2,3-/]purines 598. Compound 597 was active against P388 leukemia. Vascular relaxing effects of 598 were determined, but none showed potent activity (87CPB4031) (Scheme 123). 

Conventional and novel PKC isozymes are potently activated by phorbol esters, heterocyclic compounds found in the milky sap exuded by plants of the Euphorbiaccae family. This sap was used medicinally as a counterirritant and cathartic agent over the millennia we now know that the active ingredients, phorbol esters, specifically bind to the Cl domain, the diacylglycerol sensor described above. In fact, their ability to recruit PKC to membranes is so effective that phorbol esters cause maximal activation of conventional PKCs, bypassing the requirement for Ca2+. This module is found in a number of other proteins in addition to PKC, so the profound effects of phorbol esters on cells are mediated by other proteins in addition to PKC. 

Already in 1988 and 1991, Gao et al. [65,66] detected four different polysaccharides present in the leaves of Panax ginseng that had an effect on the complement system, but only two of them, the neutral, GL-NIa, and one of the acidic ones, GL-AIa, had potent activities at low concentrations. GL-NIa was found to be mainly an arabinigalactan type II polymer. GL-AIa was a polysaccharide with a rhamnogalacturonan core with neutral side chains of the AG-II type, confirmed by a strong reaction with the Yariv reagent and the methylation results. It was shown that the crude polysaccharide fraction contained KDO and DHA, suggesting the presence of Rhamnogalacturonan II in... 

DAG is a potent activator of protein kinase C (PKC). It has been long known that ACh causes an increase in the number of effective L-channels in many smooth muscle cells. This effect is mimicked by phorbol esters (known to activate PKC) and DAG itself Therefore, it has been suggested that one of the actions of ACh involves the activation of L-channels via the evoked increase of DAG. 

The potent activity of D-DOT against AZT- and 3TC-resistant HIV-1 strains together with its excellent pharmacokinetic profile in rhesus monkeys suggest that further development of D-DOT towards HIV-1 chemotherapy is warranted (Asif et al. 2007). 

T-1249 demonstrated substantial activity against enfuvirtide-resistant viruses in clinical studies (Melby et al. 2007a) however, development was discontinued due to formulation issues. Additional peptides with more potent activity were subsequently designed, which also showed much improved pharmacokinetic properties (Dwyer et al. 2007) however, the availability of oral agents in other new classes makes the likelihood of the development of these agents uncertain. 

IFN-y has potent activity against HCV in the subgenomic replicon system (Dash et al. 2005 Frese et al. 2002 Lanford et al. 2003). Synergistic immunomodulatory effects of IFN-ylb and IFN-a have been reported (Wang et al. 2006). However, a pilot study of IFN-y at a dose of 100-400pg three times per week showed no antiviral efficacy in patients infected with HCV genotype 1 who had not responded to standard therapy or who had relapsed (Soza et al. 2005). 

Attaching some short peptidic sequences to adamantane makes it possible to design novel antagonists. The bradykinin antagonist, which is used as an anticancer agent, is an example. The adamantane-based peptidic bradykinin analog was utilized in strucmre-activity relationship (SAR) studies on the bradykinin receptors and showed a potent activity in inhibition of bradykinin-induced cytokine release and stimulation of histamine release [142]. 

Compound (20) eventually emerged as an optimized lead (EC50 = 4nM) with satisfactory pharmacokinetic and solubility properties as well as potent activity in animal models of visceral and chronic inflammatory pain [85]. 

Maggio R, Scarselli M, Novi F, Millan MJ, Corsini GU. Potent activation of dopamine D3/D2 heterodimers by the antiparkinsonian agents, S32504, pramipexole and ropinirole. J Neurochem 2003 87 631-641. 

More recently, the challenge to formulate with consistency highly potent actives present in diminishingly low concentrations raised the bar for formulations another significant notch. Procedures and devices for safe intravitreal implantation of sustained antiviral medication have grown from the advent of new therapies for a life- and eye-threatening new disease, HIV-AIDS. 

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