Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation

Involvement of imidazoline receptors (IR) in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensives has received tremendous attention. To date, pharmacological studies have allowed the characterization of three main imidazoline receptor classes, the I1-imidazoline receptor which is involved in central inhibition of sympathetic tone to lower blood pressure, the I2-imidazoline receptor which is an allosteric binding site of monoamine oxidase B (MAO-B), and the I3-imidazoline receptor which regulates insulin secretion from pancreatic beta-cells. All three imidazoline receptors represent important targets for cardiovascular research. The hypotensive effect of clonidine-like centrally acting antihypertensives was attributed both to a2-adrenergic receptors and nonadrenergic I1-imidazoline receptors, whereas their sedative action involves activation of only a2-adrenergic receptors located in the locus coeruleus. Since more selective I1-imidazoline receptors ligands reduced incidence of typical side effects of other centrally acting antihypertensives, there is significant interest in developing new agents with higher selectivity and affinity for I1-imidazoline receptors. The selective imidazoline receptors agents are also more effective in regulation of body fat, neuroprotection, inflammation, cell proliferation, epilepsy, depression, stress, cell adhesion, and pain. New agonists and antagonists with high selectivity for imidazoline receptor subtypes have been recently developed. In the present review we provide a brief update to the field of imidazoline research, highlighting some of the chemical diversity and progress made in the theoretical studies of imidazoline receptor ligands

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

Nova grupa antimikrobnih lekova - hemija glicilciklina

Human and veterinary medicines, since the late forties of the 20th century, have increasingly used tetracyclines as broad spectrum antibiotics. The wide and long-lasting usage of all antibiotics, including tetracyclines, accordingly causes a widespread microbial resistance. At the beginning of the nineties, the synthesis of a new antibiotics' group, including tetracyclic structure showing more active antibacterial potency and widespread spectrum activity on the existing resistant microorganisms' forms, have been reported and called glycylcyclines. The group development, its chemistry and the first launched tigecycline properties will be shown in this paper.Humana i veterinarska medicina, s kraja četrdesetih godina prošlog veka, je koristila tetracikline kao antibiotike širokog spektra dejstva. Obimna i duga upotreba svih antibiotika, uključujući i tetracikline, dovela je do pojave porasta rezistencije. Početkom devedesetih godina, objavljena je sinteza nove grupe antibiotika tetraciklične strukture, te je grupa koja je pokazala najjaču antimikrobnu aktivnost, najširi spektar dejstva na postojeće rezistentne forme mikroorganizama, nazvana glicilciklini. Razvoj ove grupe antibiotika, kao i hemija i osobine prvog registrovanog tigeciklina, prikazane su u ovom radu

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

Ligandi imidazolinskih receptora

Extensive biochemical and pharmacological studies have determined three different subtypes of imidazoline receptors: I1-imidazoline receptors (I1-IR) - involved in central inhibition of sympathicus that produce hypotensive effect; I2- imidazoline receptors (I2-IR) - modulate monoamine oxidase B activity (MAO-B); I3-imidazoline receptors (I3-IR) - regulate insulin secretion from pancreatic β-cells. Therefore, the I1/I2/I3 imidazoline receptors are selected as new, interesting targets for drug design and discovery. Novel selective I1/I2/I3 agonists and antagonists have recently been developed. In the present review, we provide a brief update to the field of imidazoline research, highlighting some of the chemical diversity and progress made in the 2D-QSAR, 3D-QSAR and quantitative pharmacophore development studies of I1-IR and I2-IR imidazoline receptor ligands. Theoretical studies of I3-IR ligands have not yet been performed because of insufficient number of synthesized I3-IR ligands.Imidazolinski receptori (IR) na osnovu farmakološkog efekta podeljeni su u tri osnovne klase: I1-imidazolinski receptori (I1-IR) - učestvuju u centralnoj inhibiciji simpatikusa koja prouzrokuje sniženje krvnog pritiska; I2-imidazolinski receptori (I2-IR) - predstavljaju alosterno mesto vezivanja monoamino oksidaze B (MAO-B) i I3-imidazolinski receptori (I3-IR) - regulišu sekreciju insulina iz β-ćelija pankreasa. Zbog svoje uloge u organizmu sve tri klase imidazolinskih receptora predstavljaju veoma važno ciljno mesto za istraživanja novih lekova. Zato su prethodnih godina veoma intenzivno izučavani farmakološki efekti aktivacije I1- -IR, I2-IR i I3-IR podtipova imidazolinskih receptora i njihova povezanost sa aktivacijom drugih signalnih puteva. Nedavno sintetisani i ispitani visokoselektivni agonisti i antagonisti I1- -IR i I2-IR, omogućili su izvođenje detaljnijih teorijskih studija radi definisanja osnovnih farmakofora ovih liganada. U ovom preglednom radu biće prikazani glavni odnosi između afiniteta ka specifičnim podtipovima imidazolinskih receptora (I1-IR i I2-IR) i strukture liganada, ispitivani pomoću 2D-QSAR (quantitative structure-activity relationship) studija, 3D --QSAR studija i analize 3D-strukture farmakofore

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

Medicinska hemija inhibitora histon deactilaze 6 – in silico pristup dizajnu lekova

Hemija postranslacionih modifikacija histona, kao i njihov uticaj na ekspresiju gena predstavlja jedan od najizazovnijih procesa koji se izučava u kancerskoj epigenetici. Kovalentne modifikacije, kao što su acetilovanje i deacetilovanje histona menjaju arhitekturu hromatina i mogu dovesti do različitih ćelijskih odgovora. Od 2006. godine, registrovano je 5 inhibitora histon deacetilaza, efikasnih u terapiji hematoloških maligniteta. Medicinski hemičari posvećuju posebnu pažnju selektivnosti novodizajniranih jedinjenja ka HDAC6 izoformi, koja je jedinstveno lokalizovana u citoplazmi i utiče na dinamske procese citoskeleta. Metode dizajna lekova bazirane na hemijskim strukturama poznatih HDAC1 iHDAC6 inhibitora (pristup zasnovan na strukturi liganada) unapredile su naše razumevanje strukturnih karakteristika neophodnih za potentnu HDAC6 inhibiciju. Da bi se kvantifikovao odnos između strukture i potentnosti različitih HDAC inhibitora, primenili smo 3D‐QSAR studiju (trodimenzionalnu studiju odnosa strukture i aktivnosti) sa već publikovanim strukturama HDAC1 i HDAC6 inhibitora. Hemijska struktura skriptaida i njegovi izračunati tridimenzionalni deskriptori su korišćeni za pretragu novih fragmenata sa sličnim hemijskim osobinama kao inaftalimidno jezgo (dizajn zasnovan na strukturi fragmenta). Predviđene HDAC1 i HDAC6 aktivnosti novodizajniranih jedinjenja su dobijene korišćenjem validiranih 3D‐QSAR modela. Za dalje studije, odabrana su ona jedinjenja sa poboljšanom in silico selektivnošću usmerenoj ka HDAC6 izoformi. Način vezivanja novih jedinjenja je ispitan studijama molekulskog dokinga i upoređen sa načinom vezivanja poznatih HDAC inhibitora. Kombinovani pristupi zasnovani na strukturi liganda, fragmenata i strukturi vezivnog mesta su uspešno primenjeni u našoj grupi za pronalaženje novih i hemijskih atraktivnih HDAC6 inhibitora. Uočeno je da su predviđene aktivnosti pomoću 3D‐QSAR studije za najbolje rangirana dizajnirana jedinjenja u korelaciji sa rezultatima studije virtuelnog dokinga. Ovakav kombinovani protokol povećava šansu pronalaženja HIT jedinjenja kao selektivnog HDAC6inhibitora, što će u narednim istraživanjima biti potvrđeno in vitro studijama novosintetisanih jedinjenja u našoj laboratoriji.The chemistry of histone posttranslational modifications and their influence on gene expression present one of the most challenging processes studied in cancer epigenetics. The covalent modifications, such as histonea cetylation and deacetylation alter the chromatin architecture and lead to different cellular responses. Since 2006, there have been five histone deacetylase (HDAC) inhibitors clinically approved for the haematological cancers. Medicinal chemists pay particular attention to the selectivity of newly designed compounds against HDAC6 isoform, as it is uniquely located in the cytoplasm and controls the dynamics of the cytoskeleton. Drug design methodologies based on the known HDAC1 and HDAC6 inhibitors structures (ligand‐based approach) improved our understanding of the structural requirements needed for potent HDAC6 inhibitors. To quantify the relation between the structure and potency in a group of diverse HDAC inhibitors, we performed 3DQSAR (Quantitative Structure‐Activity Relationship) studies with published HDAC1 and HDAC6 inhibitors. The structure of scriptaid and its derived three‐dimensional descriptors were used for searching of novel fragments with the similar chemical properties as its naphthalimide core (fragment‐based design). The predicted HDAC1 and HDAC6 activities of newly designed compounds were obtained by validated 3D‐QSAR models. We selected only those compounds with improved in silico selectivity toward HDAC6 isoform for further studies. The binding modes of novel compounds were introspected by molecular docking studies and compared with the known HDAC inhibitors binding modes. The combined ligand‐based, fragment‐based and structure‐based methodologies were successively applied in our group to discover novel and chemically attractive HDAC6 inhibitors. We observed that the predicted potency of the top‐ranked designed HDAC6 inhibitors by 3D‐QSAR studies are correlated with the virtual docking results. The combined protocol increases the hit rate in the discovery of selective HDAC6 inhibitors, which will be further examined by in vitro studies of synthesized compounds in our laboratory.VII Kongres farmaceuta Srbije sa međunarodnim učešćem Zajedno stvaramo budućnost farmacije Beograd, 10-14. oktobar 201

Genotoksične nečistoće u lekovima ‐ regulatorni zahtevi

Most chemical syntheses use highly reactive molecules, which are often DNA-reactive (mutagens). They may be present in the active substance (AS) or in the drug product as genotoxic impurities (GI). The mechanism of action of most GIs is based on DNA modification by direct binding (electrophilic - alkylating agents), insertion into the DNA chain (topoisomerase inhibitors) and antimetabolites (purine/pyrimidine analogs). Structural alerts (SA) for carcinogenic activity are defined as functional groups or substructures of compounds associated with carcinogenic activity (1). SA indicates a chemical group that causes toxic effects through one or several common mechanisms of action. GIs can bind directly to DNA or after metabolic transformations (oxidation and reduction), thus the SA structure may indicate the formation of several toxic metabolites. The risk assessment for the presence of GIs is a mandatory part in the module 3 (AS/DP impurity profile) submitted in the marketing authorization procedure, also in the approval of clinical trials. Guideline ICHM7(2) provides recommendations for identification, categorization, qualification and control strategy of mutagenic impurities in order to limit the potential carcinogenic risk. According to ICHM7, the classification (class 1-5) of all impurities is performed on the basis of data on carcinogenicity and bacterial mutagenicity (BM) from databases/scientific literature. If data are not available, computational toxicological assessment (QSAR) is performed and BM is predicted with two independent models. If any of model shows SA structures, a BM assay (Ames test) is performed. The high potent mutagenic carcinogens (aflatoxins, nitrosamines, alkyl-azoxy compounds) referred to as “cohort of concern”.U većini hemijskih sinteza se koriste veoma reaktivni molekuli koji su često i DNK – reaktivni (mutageni). Oni mogu biti prisutni u aktivnoj supstanci (AS) ili gotovom proizvodu (GP) kao genotoksične nečistoće (GN). Mehanizam dejstva većine GN se zasniva na modifikaciji DNK i to direktnim vezivanjem (elektrofili - alkilujući agensi), umetanjem u lanac DNK (inhibitori topoizomeraze) i antimetaboliti (purinski/pirimidinski analozi). Upozoravajuće strukture (SA) za kancerogenu aktivnost se definišu kao funkcionalne grupe ili delovi strukture jedinjenja koje su povezane sa kancerogenom aktivnošću (1). SA ukazuje na hemijsku grupu jedinjenja koja izaziva toksične efekte kroz jedan ili nekoliko obično zajedničkih mehanizama delovanja. GN mogu direktno da se vezuju za DNK ili nakon metaboličkih transformacija (oksidacija i redukcija) pa SA struktura može da ukaže na nastanak nekoliko toksičnih metabolita. Procena rizika na prisustvo GN u delu koji se odnosi na profil nečistoća AS/GP je obavezan deo dokumentacije o kvalitetu leka koji se podnosi u postupku registracije leka, kao i odobravanja kliničkih ispitivanja. U smernici ICHM7(2) su date preporuke za identifikaciju, kategorizaciju, kvalifikaciju i kontrolnu strategiju mutagenih nečistoća kako bi se ograničio potencijalni kancerogeni rizik. Prema ICHM7 se vrši klasifikacija (klase 1-5) svih nečistoća na osnovu podataka o kancerogenosti i bakterijskoj mutagenosti iz baza i naučne literature. Ako podaci nisu dostupni sprovodi se in silico toksikološka procena (QSAR) i predviđa se bakterijska mutagenost sa dva nezavisna modela. Ako jedan od modela pokaže SA strukture, radi se test povratne mutacije na bakterijama (Ames test). Posebno se razmatraju visoko potentni mutageni kancerogeni (aflatoksini, nitrozamini, alkil-azoksi jedinjenja).VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra