Determination of the ionization constants of 2,4-DIIODO-6-methylphenyl carbamoylmethyl iminodiacetic acid

The ionization constants of 2,4-diiodo-6-methylphenylcarbamoylmethyl iminodiacetic acid were determined: pK1 1.3 (the first carboxylic group), pK2 2.52 (the second carboxylic group), pK3 5.86 (amino group) and pK4 10.85 (amide group). The determination were performed at 25o C.Physical chemistry 2004 : 7th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 21-23 September 200

Hromatografske metode za predviđanje apsorpcije leka posle oralne primene

Today with the development of combinatorial chemistry hundreds and hundreds of compounds that have potential biological activity are synthesized. The studies which include the selection of drug candidates and the study of their pharmacological properties are time consuming, expensive and usually require the use of experimental animals. For ethical and/or economical reasons, a great deal effort is currently being made to develop in vitro systems and provide primary information about the capability of new compounds in the first steps of drug development. Chromatographic models to predict drug absorption are experimentally easier than membrane-based permeability assays, because of their simplicity, accuracy and avoidance of experimental animals. Different chromatographic systems have been proposed to predict oral drug absorption. The use of conventional reversed-phase columns only has proven to provide adequate correlations for homologous series of compounds. The inclusion of amphiphilic structures in the stationary and/or mobile phases is a pre-requisite to emulate interactions of drugs with the phospholipids bilayers in the membranes.Savremeni razvoj kombinatorijalne hemije omogućio je sintezu velikog broja jedinjenja sa potencijalnom biološkom aktivnošću. Ispitivanja koja uključuju izbor jedinjenja i studije farmakoloških osobina su dugotrajna, skupa i obično zahtevaju primenu eksperimentalnih životinja. Iz etičkih i/ili ekonomskih razloga, veliki napori ulažu se u razvoj in vitro sistema koji mogu da pruže značajne informacije u ranim fazama razvoja leka. Hromatografski modeli za predviđanje apsorpcije leka su eksperimentalno jednostavni, tačni i ne zahtevaju primenu eksperimentalnih životinja. Primena reverznofaznih hromatografskih sistema dala je dobre korelacije samo za homologe serije jedinjenja. Uvođenje amfifilnih struktura u stacionarnu i/ili mobilnu fazu je bitan uslov za simulaciju interakcija farmakološki aktivnih jedinjenja sa fosfolipidnim dvoslojem u membrani

Eikozanoidi u terapiji astme

Many novel types of asthma therapeutic procedures have been investigated in the past decade. A vast amount of work in the 5-LO inhibitor and LT1-receptor antagonist area has resulted in a various of compounds being identified for clinical trails, and several compounds are used in the clinic. The impact of the LT1-receptor antagonist and 5-LO inhibitors on alergy therapy will be significant, if these compounds have an antiinflammatory effect within their mechanism. The area with possibly the most promise is selective inhibitors of phosphodiesterase enzymes (PDEs). Selective inhibitors of three isoenzymes of PDEs (PDE III, IV and V) may be possess both activity; bronchodilatory and anti-inflammatory effects. This results imply that this agents may lead to a re-examination and further subclassification of various types of asthma diseases

Hemija sintetskih antihiperglikemika

Chemistry of some non-insulin dependent diabetes mellitus (type 2) such as sulfonylurea derivatives, glinides, biguanides and thiazolidinedione is shown. The relationship between chemical structures and the molecular mechanism of action are presented.U terapiji insulin nezavisnog dijabetesa (tip 2) koriste se derivati sulfonilureje, bigvanidina, tiazolidindiona i inhibitori alfa glukozidaze. U ovom radu je prikazan odnos hemijske strukture i aktivnosti nekih sintetskih antihiperglikemika

Hemija prostanoida i antagonista CCK2 receptora

The involvement of more neurotrasmiters, hormones and autocoids in the control of gastric acid secretion has resulted in a number of therapeutic approches directed toward achieving its inhibition. Although significant progress in obtaining CCK2 gastrin receptor antagonists as vell as EP3 receptor agonists has been made in recent years, compounds from either of these groups seem unlikely to dislodge the irreversibile proton-pump inhibitors and histamine H2-angonists as the preferred treatment in acid-related disoreders at present. All of the potencially antiulcerative useful prostanoids are in general synthetically produced closely related analogs of natural prostaglandins PGE1 and PGE2. For example, it was hoped that EP3 receptor agonists such as misoprostol and newly sinthetised, selectivelly and more active GR63799X, might prove beneficial as cytoprotective agents.Učešće brojnih endokrinih hormona i neurotransmitera u kontroli gastrične sekrecije pruža mogućnost različitih terapijskih pristupa u tretiranju ulkusne bolesti i stanja hipersekrecije. Inhibitori protonske pumpe, H2 antagonisti histamina i muskarinskih receptora su veoma efikasni i bezbedni antiulkusni i antihipersekretorni lekovi. Iz ove grupe lekova u kliničkoj fazi ispitivanja su novi, reverzibilni inhibitori protonske pumpe i antagonisti H2 receptora druge generacije. U kliničkoj fazi ispitivanja nalaze se i brojni antagonisti CCK2-receptora kao potencijalni inhibitori gastrične sekrecije. Pored inhibicije gastrične sekrecije ovi potencijalni lekovi imaju i antianksiozni efekat. Citoprotektivna zaštita prostanoida, agonsta EP3 receptora za per os primenu je noviji pristup naročito u hroničnoj terapiji nesteroidnim antireumaticima koji mogu biti uzročnici ozbiljnih neželjenih efektata kao što su hipersekrecija gastritis, ulkus i gastrične hemoragije

Hemija novijih inhibitora agregacije trombocita i fibrinolitika

Heparin is being replaced in many of its applications by currently available alternative parenteral agents such as fondaparinux, leperudin, bivalirudin and argatromban. These alternative agents offer advantages in terms of more predictable pharmacokinetics and improved safety, reducing or eliminating the need for patient monitoring and reducing or eliminating the risk of heparin induced thrombocytopenia. Orally bioavialable direct thrombin and FXa inhibitors now under development, seem poised to become available over the next years and will represent viable alternative to both the parenteral anticoaguants and some currently available oral anticagulants such as warfarin, fenprocumon and acenokumarol.Oboljenja kardiovaskularnog sistema kao što su infarkt miokarda, različiti oblici tromboza i embolija, predstavljaju najznačajnije uzročnike mortaliteta i morbiteta. U savremenoj antikoagulantnoj terapiji pored klasičnih peroralnih antiagregatika kao što su: aspirin, dipiridamol i sulfinpirazon, i ne selektivnih inhibitora tkivnog faktora plazminogena, prećišćenog bakterijskog proteina, streptokinaze, reteplaze i urokinaze za parenteralnu primenu, su uvedeni selektivniji aktivatori plazminogena: alteplaza i tenekteplaza koji predstavljaju proizvode rekombinatne DNK tehnologije. Pored razvoja parenteralnih fibrinolitika, proizvoda rekombinantne tehnologije, sulfonskih polisaharidnih anjona male molekulske mase sa aktivnim pantasaharidnim sulfonatim anjonima, u prevenciji i terapiji postoperativno se koriste i peroralni antagonisti faktora koagulacije kao sto je varfarin i njegovi derivati koji predstavljaju antagoniste vitamina K. U savremenoj terapiji učinjen je napredak u prevenciji i terapiji embolija i dubokih tromboza uvođenjem u kliničku praksu lekova iz grupe malih molekula poznatih pod nazivom peptidomimetika. Dizajniranje peptidomimetika je omogućeno razvojem molekularne biologije, genetskog inženjeringa, imunohemije, biohemije i fiziologije. Razvoj ovih naučnih disciplina doveo je do utvrđivanja preciznih

Agonisti/antagonisti steroidnih receptora i bisfosfonati u supstitucionoj terapiji - molekularno-hemijske osnove

Agonists of estrogen receptors, such as esters of estradiol, conjugated estrogens and esterified estrogens have been widely used in estrogen replacement therapy. Partial agonists of estrogen receptors, derivatives of triarylethylene such as, tamoxifen and toremifene posses weak estrogen-like effects on endometrium, bone and lipids. Recent advances in molecular pharmacology and estrogen receptors have resulted in the development of selective receptor modulators (SEMSs) that activate the estrogen receptor but that also exhibit tissue-specific estrogen-agonist or -antagonist activity. The first SERM marked is the benzothiophene, raloxifene which was introduced to maintain bone density in controlling osteoporosis postmenopausal women. Bisphosphonates have been used as second-line agents for prevention and treatment of osteoporosis in postmenopausal women.U supstitucionoj terapiji kod žena koriste se hormoni steroidne strukture/ agonisti ERa i ERp estrogenih receptora: derivati estrana, estri estradiola, metaboliti estardiola - prirodni proizvodi konjugovani estrogeni i polusintetski -esterifikovani estrogeni. Pored agonista u terapiji se koriste i parcijalni agonisti steroidnih receptora, derivati trifeniletilena ili trifeniletana kao što su tamoksifen i toreksifen. Derivat rigidne biciklične strukture-benzotiofena, raloksifen, je selektivni modulator estrogenih receptora, agonista estrogenih receptora u osteoblastima i osteoklastima, a antagonista na estrogenim receptorima uterusa i dojke. U terapiji osteoporoze se koriste hemijski stabilni bisfosfonati kao što su alendronat, risendronat i dr

Novine u dizajniranju i razvoju lokalnih antiinflamatornih steroida

Topical anti-inflammatory corticosteroids are "drug of choice" in treatment of many inflammatory and allergic diseases in dermatology, pulmology, ophthalmology rheumatology and gastroenterology. Their using is limited because some serious systematic effects have been noted by longtime using of these drugs. In this manuscript, it was made a review of the relationship of structural changes on molecules of corticosteroids and intensity and specificity of their activity. Some of recently trends in design of newly anti-inflammatory steroids are based on retrometabolic design of "soft drugs", which are biotransformed to the inactive metabolits in body of patient after their applications. In manuscript, design and synthesis of new diastereoisomeric esters of steroid, as potentional antiinflammatory agents, was shown.Lokalni antiinflamatorni steroidi su "lekovi izbora" u lečenju raznih inflamatornih i alergijskih oboljenja u dermatologiji, pulmologiji, oftalmologiji, reumatologiji, gastroenterologiji. Dugotrajnom primenom ovih lekova mogu nastati veoma ozbiljni sistemski neželjeni efekti koji ograničavaju njihovu upotrebu. U ovom radu, dat je pregled uticaja strukturnih promena, u molekulama lokalnih antiinflamatornih steroida, na jačinu i specifičnost antiinflamatornog dejstva, a sve u cilju dobijanja novih bezbednijih lekova. Jedan od savremenih trendova u dizajnu antiinflamatornih steroida zasniva se na retrometaboličkom pristupu "soft" lekova, koji se nakon ispoljavanja dejstva, u organizmu pacijenta biotransformišu do neaktivnih i netoksičnih metabolita. U radu je prikazan dizajn i sinteza novih diastereoizomernih estara antiinflamatornih steroida kao potencijalnih lekova u lokalnoj terapiji

Synthesis and RP-TLC lipophilicity evaluation of a novel fluocinolon acetonide soft drug derivative

Cortienic acid was obtained by periodic acid oxidation of fluocinolone acetonide, whereas corresponding amide was synthesized from the cortienic acid and ethyl ester of b-alanine by dicyclohexylcarbodiimide - hydroxybenzotriazole coupling procedure. Lipophilicity of the amide was evaluated by using reversed-phase thin-layer chromatography systems, consisting of ethanol and water in various ratios, and was higher in comparison to fluocinolone acetonide and cortienic acid

Crystal and Molecular Structure of 3B-Hydroxy-14,15B-epoxy- 5\u27B,14B-card-20,22-enolide (Digirezigenin)

The title compound C23H3204 and its methyl-suberate ester were discovered in Ch\u27an Su, the dried venom of the Chinese toad. Its crystals are orthorhombic, space group P21212i, and quasi- isostructural with those of the related compound digitoxigenin (C23H340 4) . The structure was solved by direct methods and refined by least squares technique to a conventional R index of 0.059 for 2271 unique diffractometer observations. The presence of the rigid 14, 15~-epoxy ring alters considerably the shape of ring D (17E) relative to that in digitoxigenin (14E). However, it has little effect upon the general features of the 14-iso-aethiocholane skeleton and the conformation of the y-lactone ring. The amount of rotation about the C(l 7)-C(20) bond is hardly changed while the distance between the position of the carbonyl O relative to digitoxigenin is only 33.2 pm. The conformation of the title compound is also compared with that of a bufa-20, 22-dienolide (cinobufagin) which also possesses a 14, 15~-oxirane ring