Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors

Sinteza N4-(2,4-dimetilfenil) semikarbazona kao inhibitori 4-aminobutirat aminotransferaze

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formations. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models including maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain -aminobutyric acid levels and in vitro -aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest these compounds to exhibit anticonvulsant activity via GABA-mediated mechanism.Sintetizirano je nekoliko 2,4-dimetilfenil supstituiranih semikarbazona u tri sintetska koraka koji uključuju aril uree i aril semikarbazide. Strukture spojeva su potvrđene spektroskopskim metoda i elementarnom analizom. Ispitano je antikonvulzivno djelovanje novih spojeva nakon izazivanja konvulzija elektrošokom te supkutanom primjenom pentilentetrazola ili strihnina. Osim toga, testirano je antidepresivno djelovanje te učinak tih spojeva na ponašanje štakora. Praćen je njihov utjecaj na koncentraciju gama-aminomaslačne kiseline (GABA) u mozgu štakora te in vitro na aktivnost gama-aminobutirat transaminaze (Pseudomonas fluorescens). Preliminarni pokusi ukazuju da antikonvulzivno djelovanje ovih spojeva uključuje GABA-ergički sustav

Sinteza N4-(2,4-dimetilfenil) semikarbazona kao inhibitori 4-aminobutirat aminotransferaze

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formations. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models including maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain -aminobutyric acid levels and in vitro -aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest these compounds to exhibit anticonvulsant activity via GABA-mediated mechanism.Sintetizirano je nekoliko 2,4-dimetilfenil supstituiranih semikarbazona u tri sintetska koraka koji uključuju aril uree i aril semikarbazide. Strukture spojeva su potvrđene spektroskopskim metoda i elementarnom analizom. Ispitano je antikonvulzivno djelovanje novih spojeva nakon izazivanja konvulzija elektrošokom te supkutanom primjenom pentilentetrazola ili strihnina. Osim toga, testirano je antidepresivno djelovanje te učinak tih spojeva na ponašanje štakora. Praćen je njihov utjecaj na koncentraciju gama-aminomaslačne kiseline (GABA) u mozgu štakora te in vitro na aktivnost gama-aminobutirat transaminaze (Pseudomonas fluorescens). Preliminarni pokusi ukazuju da antikonvulzivno djelovanje ovih spojeva uključuje GABA-ergički sustav

The impact of targeting TRAF2 and NCK-interacting protein kinase (TNIK) on anti-tumor effect in small cell lung cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1056/thumbnail.jp

Validating DLL3-targeting CAR T in small cell lung cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1022/thumbnail.jp

Effect of intravenous dexmedetomidine administered as bolus or as bolus-plus-infusion on subarachnoid anesthesia with hyperbaric bupivacaine

Background: Subarachnoid anesthesia is a widely practiced regional anesthetic for infraumbilical surgeries. Intravenous dexmedetomidine is known to prolong both sensory and motor blockade when administered along with subarachnoid anesthesia. Material and Methods: Seventy-five patients scheduled to undergo elective infraumbilical surgeries under subarachnoid anesthesia were randomly allocated to one of the three groups. Group B received intravenous saline over 10 min followed by 12.5 mg intrathecal bupivacaine and then intravenous saline over 60 min. Group bupivacaine + dexmedetomidine bolus (BDexB) received intravenous dexmedetomidine (1 μg/kg) over 10 min followed by 12.5 mg intrathecal bupivacaine and then intravenous saline over 60 min. Group bupivacaine + dexmedetomidine bolus-plus-infusion (BDexBI) received intravenous dexmedetomidine (0.5 μg/kg) over 10 min followed by 12.5 mg intrathecal bupivacaine and then intravenous dexmedetomidine (0.5 μg/kg) over 60 min. Onset of analgesia (at T10), complete motor block (Bromage score 3), and highest level of analgesia were noted. Sensory and motor levels were checked periodically till sensory recovery (at S2–S4) and complete motor recovery (Bromage score 0). Ramsay sedation score and incidence of bradycardia/hypotension were noted. Results: Sensory recovery was significantly longer in Group BDexB (303 min) and Group BdexBI (288 min) as compared to Group B (219.6 min). Motor recovery was also significantly prolonged in Group BDexB (321.6 min) and Group BDexBI (302.4 min) as compared to Group B (233.4 min). Patients receiving dexmedetomidine were sedated but were easily arousable. Conclusion: Intravenous dexmedetomidine given as bolus or bolus-plus-infusion with intrathecal hyperbaric bupivacaine prolongs both sensory and motor blockade

Nitric oxide synthase regulation and diversity: implications in Parkinson's disease

Nitric oxide (NO) is a janus faced chemical messenger, which, in the recent years, has been the focus of neurobiologists for its involvement in neurodegenerative disorders in particular, Parkinson's disease (PD). Nitric oxide synthase, the key enzyme involved in NO production exists in three known isoforms. The neuronal and inducible isoforms have been implicated in the pathogenesis of PD. These enzymes are subject to complex expressional and functional regulation involving mRNA diversity, phosphorylation and protein interaction. In the recent years, mRNA diversity and polymorphisms have been identified in the NOS isoforms. Some of these genetic variations have been associated with PD, indicating an etiological role for the NOS genes. This review mainly focuses on the NOS genes-their differential regulation and genetic heterogeneity, highlighting their significance in the pathobiology of PD