Endothelin Antagonist – Drug Development Example

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"Endothelin Antagonist " is a controversial example of medical research on drug development. The drug discovery is initiated by the unmet clinical needs and clinical conditions lacking suitable treatments. The process of drug discovery is not a simple one. It is a complex process that may take up to a decade and a half. The first step to the discovery is an idea that arises from conceptualization and serious brainstorming. This is followed by building a concrete hypothesis o release a new form of the drug to the markets (Hughes et al, 2011).

  The process begins with approximately 10,000 compounds but ultimately ends up at only one drug reaching the markets. It is the process of major contribution is drug metabolism and pharmacokinetics (Palmer, 2003). One of the fundamental processes discoveries of drugs is screening cascade, which relies on the activity of the drug on a specific target with affinity to particular receptors. This is besides the potency of the drug side by side with the bioavailability of the drug when test it in vivo. Moreover, with drug metabolism, if it takes orally or intravenously and its half-life, these are going parallel with a reasonable dose for patient compliance (Claxton, Cramer, and Pierce, 2001). Endothelin Antagonist A vasoconstrictive peptide referred to as endothelin is physiologically secreted by the endothelial cells.

The receptors are expressed as ETA and ETB and are present in a whole-body or overproduced in a pathophysiology condition that affects many systems and influences blood pressure centrally and peripherally. This condition is treatable by the use of endothelin antagonists. With the use of the antagonist, the discovery of drugs increases the chances of survival of hypertensive patients.

It also controls the condition of hypertension quite well (Kohan 2010). This workshop intends to bring forward the design of a drug that antagonizes the endothelin effect. It will involve the screening of 500,000 compounds. The approximate budget for the whole process is a million dollars and the process is expected to take at least three months.   The elimination method has been employed to discard the unwanted compounds in a step-by-step approach to ultimately end up with the most compatible compounds. The Discussion Result Binding assay Table 1: Test 1 results: Activity in ETA receptor binding assay % INHIBITION COMPOUND 100 LN-208 100 LN-015 90 LN-142 95 LN-292 60 LN-127 95 LN-216 90 LN-047 60 LN-209   A test has been conducted on the affinity to assist in the estimation of the antagonist activity of completing the binding sites of the receptors by displacement of the ligand.

The concentration of the test was found to be 1*10-4 M. All other compounds were rejected since the percentage of inhibition was ≥ 10%. This percentage was considered very low and unsuitable for making ETA antagonist. Activity in high throughput screen Table 2:Test 2 results: Activity in high-throughput screens (A=active I=inactive) compound %inhibition PDE ECE CETP SH2 LN-208 100 A I I I LN-015 100 A A A A LN-142 90 I I I A LN-292 95 I I I I LN-127 60 I I I I LN-216 95 I I I I LN-047 90 I I A I LN-209 60 I I I I   Three compounds have been eliminated in the screening for the activity of the compound in a high throughput screen.

These three compounds are LN-209, LN-216, and LN-015. In the first case, one the inhibition percentage stood at 60% which could not suffice as it was considered low. Therefore, so it is not highly potent. Moreover, its structure consists of a sulfoxide group that is not preferable for use because of its metabolizing action. On the other hand,   LN-216 had a high potency of 95% and is mainly peptide. The biggest problem is faced with peptides is their low bioavailability if they were orally taken unless a modification of compounds is done.

The problem is caused by systemic enzymatic degradation and poor penetration of the intestinal membrane (Morishita and Peppas, 2006). The final one, LN-015 had the highest inhibition of 100%. However, it is also not preferred for use because of its lack of selectivity. This implies that it binds to all receptors PDE, ECE, CETP, and SH2 which could lead to an increase of its side effects. IC50 Table 3:Test 3 results: IC50 determination for ETA Receptor Binding Compound PIC50 LN-208 7 LN-142 8 LN-292 8 LN-127 < 4 LN-047 7   PIC50, a log IC50 is the half concentration and requires an inhibition.

It is of profound assistance in the determination of the antagonist drug potency.   A high amount of PIC50 leads to the high effectiveness of the inhibition and vice versa. According to these facts, LN-127 with PIC50< 4 is the one that will be expelled at this process. On the contrary, the other compounds will remain to be tested further. PA2 value Table 4: Test 4 results: pA2 Determination in Rat Aortas Compound pA2 LN-208 7 LN-142 8 (also contracts tissue) LN-292 8 LN-047 7   The table above reveals the results of the PA2 value of the four remaining compounds.

PA2 refers to the negative logarithm to base 10 of the molar concentration of an antagonist and requires doubling of the concentration of the antagonist needed to reach the maximum response of it. As such, the higher PA2 value reflects the smaller concentration needed to antagonize the ligand (Neubig, Spedding, Kenakin, and Christopoulos 2003). At this step, all compounds express a high PA2. However, LN-142 has been rejected due to its action on tissue - tissue contraction - while the rest of the three compounds will be utilized to conduct further investigations.     I. V activity Table 5: test 5 results: I.V.

Activity in Anaesthetized Rats Compound ID50 LN-208 inactive LN-292 0.1mg/kg LN-047 0.5mg/kg   It is clearly shown in the above table that ID50 of the compounds were determined, thereby implying the dose required to inhibit 50% of the ligand. Small ID50 indicates the potency of the antagonist. The process was conducted in vivo, hence inactivity action of LN-208 maybe resulted in that drug has been metabolized to an inactive form. Accordingly, LN-208 had been rejected. Oral activity Table 6: test 6 results: Oral activity in conscious rate Compound ID50 LN-292 100 mg/kg LN-047 1mg/kg   A test on the oral bioavailability of the two compounds was conducted.

It was detected that LN-292 requires a potentially higher dose to inhibit 50% of ligand than LN-047. First, pass metabolism or degrading in the stomach could be responsible for giving rise to the incidence. As a result, LN-292 was discarded. Duration of action Table & : test 7:Oral duration of action in conscious rats was conducted for the LN-047 Duration (hour) 0.5 1 3 5 % inhibition 50% 30% 10% 0%   According to table 7, the t1/2 that is the time in which drug is eliminated by half is very small, specifying that the drug should be taken more frequently to maintain the effect of it. Conclusion: From the foregoing, LN-047 was the drug that attained the maximum affinity, potency, and bioavailability as long as an activity very smoothly and successfully.

It is worth noting, however, that the short half-life could make it not preferable for use unless and until a formulation of dosage is done carefully. This dosage formulation will guarantee its usage and increase the dosage intervals.


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