Ssri structure activity relationship of imatinib

Escitalopram - DrugBank

ssri structure activity relationship of imatinib

Proposed Mechanism of CYP3A4 Inactivation by the Tricyclic Antidepressant From a SAR standpoint, nilotinib is structurally related to imatinib and is a. Bupropion is a unique antidepressant drug. It is the In addition to the traditional structure-activity relationship studies, molecular modeling is the most Dasatinib can be regarded as a pharmacological analogue of imatinib. Despite distinct structural differences between compounds in this class, SSRIs possess similar pharmacological activity. During acute use, SSRIs block serotonin reuptake and increase serotonin stimulation Imatinib, The risk or severity of QTc prolongation can be increased when Imatinib is combined with Escitalopram.

ssri structure activity relationship of imatinib

But citalopram can also be viewed as a constrained analogue of paroxetine. Researches has shown that nearly all the activity resides in the S -enantiomer and that R -citalopram actually counteracts the action of the S -enantiomer.

The combination of the two enantiomers is known as racemic citalopram and has weak antihistaminic properties that reside in the R -enantiomer.

ssri structure activity relationship of imatinib

Solution to improve the properties of racemic citalopram is to remove the unwanted R -enantiomer. This change appears to remove the antihistaminic properties of the drug.

By removing the R -enantiomer, the lowest dose of escitalopram becomes more efficacious and faster onset than comparable dose of citalopram, where escitalopram has twice the activity of citalopram and is at least 27 times more potent than the R -enantiomer. The compound was named sertraline figure 8.

It is possible that only modest inhibition of DAT and NET is needed to cause an increase in energy, motivation and concentration, specially when added to other activity such as SERT inhibition.

Such information is very important for the understanding of essential aspects of the drugs action, ranging from selectivity profile to therapeutic efficacy and the development of new and improved drugs that target the human SERT.

Comparative molecular modeling have been used in research to create structural models of human SERT in complex with its ligand but has not given good results because of low phylogenetic and functional similarity between human SERT and available template proteins. SERT contains approximately amino acids that are predicted to form 12 transmembrane alpha-helixes TMs which are connected with intra- and extracellular loops ILs and ELs. Therefore, the crystal structure of LeuT and its transport mechanism have been proven to be a good model system for the study of NSS proteins.

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Conversely, there could be differences in their binding where the other part of the drug molecule will likely bind to SERT in a different way, given the diversity in their structure. The halogens additionally make Van der Waals interaction with Leu29 and Tyr, where the S -enantiomer additionally binds to Phe and makes Van der Waals contact with it among with previously mentioned amino acids. Because of the S -enantiomers opposite chirality to the R -enantiomer the rest of the molecule is reversed in the HBP, where the amine tail points towards the extracellular space and interacts with the N-terminal of Leu, Asp and Ala amino acids which are a part of the TM In this LeuT bound form the complex is rather rigid.

The methylphenoxy ring rotates about the O5-C6 bond by 46 degrees for the R -enantiomer and 16 degrees for the S -enantiomer, but rigidity in the molecular structure indicates that the drug maintains its low-energy configuration upon binding to its protein target. However, acute overdose can cause severe hepatic damage. Acetylsalicylic acid aspirin is also one of the oldest drugs and, contrary to acetaminophen, its mechanism of action is partly known: A more potent derivative with a better adverse effect profile would be advantageous.

Aripiprazole is a relatively new antipsychotic drug which acts as a dopamine partial agonist for the treatment of schizophrenia.

ssri structure activity relationship of imatinib

A more effective drug is needed for the treatment of refractory patients, to improve treatment of negative symptoms and cognitive dysfunction. Bupropion is a unique antidepressant drug. It is the first non-nicotine medication for the treatment of smoking cessation. Ezetimibe is a relatively new cholesterol absorption inhibitor. Its mechanism of action was discovered only recently Analogue-based drug research is underway. Lamotrigine, topiramate, and valproate are widely used anticonvulsant drugs, whose mechanism of action is not known.

Several efforts have been made to find better analogues, so far without positive results. Metformin is already an old standalone drug for the treatment of type 2 diabetes. It is used alone or in combination with new antidiabetic agents.

  • Development and discovery of SSRI drugs
  • Paroxetine
  • Sertraline

Its mechanism of action is not known which makes it difficult to conduct an analogue-based drug research. In addition to the traditional structure-activity relationship studies, molecular modeling is the most important method that the medicinal chemist can use to find a new drug analogue.

The chapter discusses several useful examples of molecular modeling in analogue research. Patenting activity is one of the basic tasks of drug research.

Patents mostly concern a group of direct analogues; therefore, the first claim of a patent contains a general structure which describes this group of compounds. The chapter gives an overview of some of the issues that can affect the commercial protection of the discoveries made by medicinal chemists. Analogue Classes The second chapter on Analogue Classes describes the following nine categories of analogues.

The discovery of dipeptidyl peptidase IV inhibitors opens a promising chapter for the treatment of type 2 diabetes. The pioneer drug sitagliptin has been followed by several analogues in order to obtain more potent and longer-acting derivatives.

Serendipitious clinical observation afforded the pioneer drug sildenafil. Several analogues have been found that have optimized its properties e. Rifamycins are antibacterial antibiotics derived from fermentation. Analogue-based drug research afforded more potent derivatives. One of the derivatives, the poorly absorbed rifaximin, has a promising application for the treatment of irritable bowel syndrome. Three analogue classes of monoterpenoid indole alkaloids are discussed: The succesful natural product direct analogues are applied to the treatment of cerebral insufficiencies and cancer.

The natural product doxorubicin is an anthracycline antibiotic used to treat a wide range of cancers but it has a cardiotoxic adverse effect.

Development and discovery of SSRI drugs - Wikipedia

The research into direct analogues had a goal to obtain drugs with a better therapeutic index. Paclitaxel and epothilone analogues are also examples of how natural product drugs can be used to initiate analogue-based drug research to afford new drug analogues with better properties as anticancer agents.

The selective serotonin reuptake inhibitors SSRIs are pharmacological analogues that revolutionized antidepressant therapy. The structurally different SSRIs have different profiles for inhibiting uptake of the neurotransmitters serotonin, dopamine, and norepinephrine.

The modification of naturally occurring tropane alkaloids afforded the quaternary ammonium salts ipratropium and tiotropium, which are important drugs used for treating chronic obstructive pulmonary disease. Tiotropium—as a result of analogue-based drug discovery—has a longer duration of action that enables a once daily dosing.

From isoprenaline isoproterenol through the selectively acting salbutamol, and on to salmeterol, analogue research resulted in selective, more potent, and longer-acting analogues with different PK profiles, which are important drugs in asthma therapy.

Case Histories In the final section of the book, eight case histories are described by their inventors.


Liraglutide is a new antidiabetic drug, an analogue of the natural product glucagon-like peptide 1. Among the acylated GLP-1 analogues liraglutide has been developed for a once-daily treatment. Eplerenone is a spironolactone analogue for treating hypertension that has a greater selectivity for the mineralocorticoid receptor and reduced sexual side-effects.

Clevudine is a new drug for the treatment of the chronic hepatitis B virus HBV infection, which belongs to the class of nucleoside reverse transcriptase inhibitors. Tipranavir is a new anti-HIV agent that is a protease inhibitor. The discovery of tipranavir used structure-based and fragment-based drug design and its long discovery process started from warfarin, which is a weak HIV-1 protease inhibitor. Dasatinib can be regarded as a pharmacological analogue of imatinib.