Target-directed pharmacology

Given that thrombin is the central mediator of coagulation and amplifies its own production, it is a natural target for pharmacologic intervention. Direct thrombin inhibitors (DTIs) bind thrombin and prevent interactions with its substrates (Fig. 7-7). Several injectable DTIs are approved for use in the United States including lepirudin, bivalirudin, arga-troban, and desirudin. Several oral DTIs are currently in... 

More recently the concept of ADMET profile (Absorption Distribution Metabolism Excretion Toxicity profile) has further streamlined the molecular pharmacology aspects of these drugs with the ultimate objective of providing efficient target directed drugs with least toxicity. 

In the clinic, PK/PD relationships with the direct pharmacological effect, reduction of target mRNA and protein as the response measure, have been demonstrated in two studies with 2 -MOE partially modified ASOs [42, 50]. In a Phase Ila study in patients with rheumatoid arthritis, ISIS 104838 was targeted at the mRNA of TNF-a (a cytokine which is important in immune response and inflammation). The results showed that TNF-a mRNA and protein reduction in synovial tissue biopsies correlated positively with concentrations of ISIS 104838 in the synovial tissues [50]. Another investigation of PK/PD relationships was conducted in a Phase II doseranging study in prostate cancer patients treated with OGX-Oll, a 2 -MOE partially... 

Gurm HS, Bhatt DL. Thrombin, an ideal target for pharmacological inhibition a review of direct thrombin inhibitors. Am Heart J 2005 I49 S43-S53. 

Furthermore, it was observed that the oxime HI-6 might show direct pharmacological effects in the cholinergic nervous system in skeletal muscles. It has been found that HI-6 reduces the miniature endplate potentials and increases the quantal content by a dose-dependent decrease in the miniature endplate potential amplitude (Melchers et al., 1991). Other possible explanations have been suggested for oximes at other targets in the nervous system, such as... 

Yu H, Jin H, Gong W, Wang Z, Liang H (2013) Pharmacological actions of multi-target-directed evodiamine. Molecules 18 1826-1843... 

Pharmacological actions of multi-target-directed indole alkaloid evodi-amine 13MOL1826. 

Although PLAj activity is the first step for prostanoid biosynthesis and can limit their availability, it is not the rate-limiting step in prostanoid formation. However, direct inhibition of PLA could potentially block the production of all eicosanoids, making it a desirable target for pharmacological intervention (Yedgar et al., 2000). 

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