Presentation on theme: "Synthesis, functions and"— Presentation transcript:
1Synthesis, functions and Prostaglandins:Synthesis, functions andinhibitorsCarol S. Lutz, Ph.D.Lecture 23March 16, 2015
2Objectives:Discover and distinguish relationships betweendifferent types of eicosanoid molecules(PGs, TXs, LTs)Gain knowledge of enzymes that create PGsand TXs (COX-1 and -2)Explore physiological functions of these moleculesAscertain how pharmacological inhibitors work toblock activity
3Prostaglandins and related compounds (thromboxanes and other eicosanoids): - Potent cell signalling molecules – paracrine hormones- Multiple effects, including pain and inflammation associated with arthritisSynthesized from essential dietary fatty acids, esp. linoleic acid
4Prostaglandins: -discovered in the 1930s by Ulf von Euler -synthesized in virtually every cell in the body-unsaturated 20 carbon molecules,also contain a 5-member ring-work right within the cells where theyare synthesized—”act locally”-have an extremely short half-life and arenot stored
5Examples of prostaglandin structures -note the similarities and differencesLippincott Fig 17.21
6The first step in the synthesis of prostaglandins is the oxidative cyclization of free arachidonic acidto yield PGH2 by prostaglandinendoperoxide synthase. PGH2is converted to a variety ofprostaglandins and thromboxanesby a variety of cell-specificsynthases.Note: Two catalytic activitiesLippincott 17.22
7Cyclo-oxygenase Isoforms (COX-1 vs COX-2) Two isoforms of COXBoth produce prostaglandins (PGE2, PGF2a, PGI2)COX-1 is constitutive, expressed in most tissuesphysiological and homeostatic role, cell signallingnot influenced by steroid administrationnot increased by cytokines nor bacteriaCOX-2 is inducible following inflammation, trauma, etcfound in immunocompetent cells (e.g. leukocytes)pathophysiological role, maintains inflammationinduced by cytokines (interleukin-1)inhibited by steroids
14Functions of prostaglandins Activation of the inflammatory response, production of pain,and fever. When tissues are damaged, white blood cells aremobilized to the site to minimize tissue destruction.Prostaglandins are produced as a result.2. Blood clots form when a blood vessel is damaged. Closelyrelated molecules called thromboxanes stimulate constrictionand clotting of platelets. Conversely, PGI2 is produced to havethe opposite effect on the walls of blood vessels where clotsshould not be forming.
15Functions of prostaglandins, cont. 3. Certain prostaglandins (i.e. PGE2) are involved with inductionof labor by inducing uterine contractions.4. Prostaglandins are involved in several other organs-regulate salt and fluid balance in body-increase blood flow in kidneys-increase secretion of protective mucus in GI tract-inhibit acid synthesis in GI tract-leukotrienes, related molecules, promote constriction ofbronchi associated with asthma
17How do NSAIDs work? Summary Inhibit COX enzymesReduce production of prostaglandins and thromboxanesReduce pain, fever and inflammationBut…Side effects of some NSAIDs in some people- include gastrointestinal irritation, ulcers, bleeding, etc.- if untreated, lead to death (~16,000/yr in US)- led to hunt for better anti-inflammatory drugs
18Effects of aspirin and other pain killers? Aspirin works on both COX-1 and COX-2 to inhibitarachidonic acid’s entry into the active site of the enzyme--acetyl group of aspirin binds to serine in COX-- by blocking the activity of the COX enzymes, thisrelieves some of the effects of pain and fever--”nonselective”--many side effectsTylenol—thought to have effects through inhibitingthe activity of COX-3, an alternatively spliced formof COX-1
19Low dose aspirin therapy: Aspirin irreversibly inhibits COX-1 (and COX-2)Has a short half-lifeNew platelets are constantly being madeWill therefore reduce but not abolish the abilityfor blood to clot, thereby reducing heartattacks and stroke
20Short History of COX-2 Inhibitors (1) 1970’s - aspirin target identified as cyclo-oxygenase(COX)1980’s - Two forms of COX identified:COX-1, constitutiveCOX-2, induced at sites of inflammation- Hypothesis: selective inhibition of COX-2 mightreduce inflammation without the GI side effects.1990’s - Rational design of COX-2 inhibitors
21Rational Drug Design (1) Based on molecular and structural studies, informed by cell biology, physiology, pharmacology, etc.
22Rational Drug Design (2) Non-selective NSAIDsSelective COX-2 inhibitorsCOX-1COX-2
23COX-2 inhibitors Coxibs – a new class of NSAIDs Vioxx (rofecoxib) – withdrawn from sale by Merck,September 30, 2004Arcoxia (etoricoxib) – successor to Vioxx? Not (yet) approvedin USMerckPfizerCelebrex (celecoxib) – FDA recommended ‘black box’ warninglabelBextra (valdecoxib) –withdrawn from the market, 2005
24Short History of COX-2 Inhibitors (2) mid 1990’s - X-ray crystal structures showed that COX-2 active site has a sidepocket that is absent in COX-1.late 1990’s - inhibitors designed that preferentially bind COX-2, are equallyeffective as NSAIDs, but are reported to cause less GI damage.1998/ Celebrex and Vioxx approved by FDA for osteoarthritis andrheumatoid arthritis.2000’s next generation of drugs developed with even higher selectivityfor COX-2 over COX-1.Triumph for rational drug design
25Freedom from GI side effects make the COX-2 inhibitors very attractive…….
26Short History of COX-2 Inhibitors (3) How the problems came to lightJune 2000-VIGOR trial-compared Vioxx to naproxen-could not tell ifVioxx was bad or naproxen was protectiveSept. 30, APPROVe trial (Adenomatous Polyp Prevention on Vioxx)led Merck to withdraw Vioxx voluntarily.Randomized, placebo-controlled trial (2606 patients, for Vioxx use inpreventing colorectal polyps) showed an increased risk of heart attackand stroke.The increased risk is now estimated as 2.3-fold (from a meta-analysis).Dec. 20, APC trial (Adenoma Prevention by Celecoxib) byPfizer reported ~ 2.5-fold increase in major fatalor non-fatal cardiovascular events.
27Summary Prostaglandins, thromboxanes and leukotrienes are known as eicosanoidsThey are produced in small amounts in almost all tissues,act locally, and have many important physiological andpathological functionsThe dietary precursor of eicosanoids is the essential fatty acid,linoleic acidSynthesis of prostaglandins begins with oxidative cyclizationof free arachidonic acid to yield PGH2 by prostaglandinendoperoxide synthase (cyclooxygenase)There are two isozymes of the synthase: COX-1 and COX-2,which are important drug targets