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A rare occurrence of disseminated herpes simplex virus infection with hepatitis in an adult renal transplant recipient is described. [ABSTRACT FROM PUBLISHER]

The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library. Independent systematic examination of the aryl and heteroaryl groups resulted in compounds with enhanced potency and improved physico-chemical properties culminating in the identification of 16 (PHA-758454). In the presence of acetylcholine, 16 enhanced evoked currents in rat hippocampal neurons. In a rat model of impaired sensory gating, treatment with 16 led to a reversal of the gating deficit in a dose-dependent manner. These results demonstrate that aryl heteroaryl ureas, like compound 16, may be useful tools for continued exploration of the unique biology of the α7 nicotinic acetylcholine receptor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Determination of the feeding history of polyphagous insect pests, such as noctuid moths (Lepidoptera: Noctuidae), is a critical element in developing population and resistance management strategies for such pests. To identify reliable markers for larval host plant determination and to develop simple extraction and detection methods, a metabolomics approach was implemented after acid hydrolysis of adult moth samples. We identified a derivative from cotton metabolites as a marker in adult moths that were fed cotton tissues as a larval diet, and we propose that the marker is tricycloheliocide H 4 based on NMR and mass fragmentation analysis. Using this derivative from cotton metabolites as a marker, a targeted LC-MS/MS method reliably identified cotton as a larval diet in extracts of three noctuid moth species: Helicoverpa zea (cotton bollworm), Chloridea (Heliothis) virescens (tobacco budworm) and Chrysodeixis includens (soybean looper). We are using similar approaches to identify markers for other host plants including soybean.

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties., Competing Interests: The authors declare no competing financial interest.

We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu 5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu 5 NAMs. Increasing the sp 3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu 5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.

Novel mechanisms of action and new chemical scaffolds are needed to rejuvenate antibacterial drug discovery, and riboswitch regulators of bacterial gene expression are a promising class of targets for the discovery of new leads. Herein, we report the characterization of 5-(3-(4-fluorophenyl)butyl)-7,8-dimethylpyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione (5FDQD)-an analog of riboflavin that was designed to bind riboswitches that naturally recognize the essential coenzyme flavin mononucleotide (FMN) and regulate FMN and riboflavin homeostasis. In vitro, 5FDQD and FMN bind to and trigger the function of an FMN riboswitch with equipotent activity. MIC and time-kill studies demonstrated that 5FDQD has potent and rapidly bactericidal activity against Clostridium difficile. In C57BL/6 mice, 5FDQD completely prevented the onset of lethal antibiotic-induced C. difficile infection (CDI). Against a panel of bacteria representative of healthy bowel flora, the antibacterial selectivity of 5FDQD was superior to currently marketed CDI therapeutics, with very little activity against representative strains from the Bacteroides, Lactobacillus, Bifidobacterium, Actinomyces, and Prevotella genera. Accordingly, a single oral dose of 5FDQD caused less alteration of culturable cecal flora in mice than the comparators. Collectively, these data suggest that 5FDQD or closely related analogs could potentially provide a high rate of CDI cure with a low likelihood of infection recurrence. Future studies will seek to assess the role of FMN riboswitch binding to the mechanism of 5FDQD antibacterial action. In aggregate, our results indicate that riboswitch-binding antibacterial compounds can be discovered and optimized to exhibit activity profiles that merit preclinical and clinical development as potential antibacterial therapeutic agents., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.

Objectives: Although numerous studies have documented linkages between childhood sexual abuse (CSA) and later sexual revictimization, mechanisms underlying revictimization, particularly assaults occurring in the context of substance use, are not well-understood. Consistent with Traumagenic Dynamics theory, the present study tested a path model positing that lowered perceptions of sexual control resulting from CSA may be associated with increased sex-related alcohol expectancies and heightened likelihood of risky sexual behavior, which in turn, may predict adult substance-related rape., Methods: Participants were 546 female college students who completed anonymous surveys regarding CSA and adult rape, perceptions of sexual control, sex-related alcohol expectancies, and likelihood of engaging in risky sexual behavior., Results: The data fit the hypothesized model well and all hypothesized path coefficients were significant and in the expected directions. As expected, sex-related alcohol expectancies and likelihood of risky sexual behavior only predicted substance-related rape, not forcible rape., Conclusions: Findings suggested that low perceived sexual control stemming from CSA is associated with increased sex-related alcohol expectancies and a higher likelihood of engaging in sexual behavior in the context of alcohol use. In turn these proximal risk factors heighten vulnerability to substance-related rape. Programs which aim to reduce risk for substance-related rape could be improved by addressing expectancies and motivations for risky sexual behavior in the context of substance use. Implications and future directions are discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Blue-light phototherapy has become important in the treatment of many dermatologic conditions and as a result continue to be developed. Although blue-light therapy is successful, research shows that excessive ocular blue-light exposure may contribute to age-related macular degeneration and other vision problems. As blue-light therapy becomes increasingly more popular for clinical and at-home use, patients and operators of blue-light devices should be aware of its associated ocular hazards. Protective eyewear should be carefully selected and implemented with each therapy session to guard against the development of retinal disease., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examined as part of lead optimization efforts in drug discovery. Likewise, avoidance of "structural alerts" is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards associated with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addition, the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a molecule that contains a structural alert (RM positive or negative) a cause for concern? Could the molecule in its parent form exert toxicity? Can a low dose drug candidate truly mitigate metabolism-dependent and -independent idiosyncratic toxicity risks? In an effort to address these questions, we have retrospectively examined 68 drugs (recalled or associated with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochemical characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our analysis revealed that a significant proportion (∼78-86%) of drugs associated with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these molecules. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochemical properties such as molecular weight, lipophilicity, etc. Approximately half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chemical architecture, and many were found to be RM-positive. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely associated with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addition, competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-positive drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our analysis suggests a need for a more integrated screening paradigm for chemical hazard identification in drug discovery. Thus, in addition to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compound(s)) for lead compounds, effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compound liabilities. However, the prospective use of such data in compound selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiological mechanisms associated with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the associated "body burden" of the parent drug and its metabolites will remain an overarching goal in drug discovery.

In previous studies, number of sexual partners and sexual assertiveness were examined as independent risk factors for sexual victimization among college women. Using a sample of 335 college women, this study examined the interaction of number of sexual partners and sexual assertiveness on verbal sexual coercion and rape. Approximately 32% of the sample reported unwanted sexual intercourse, 6.9% (n = 23) experienced verbal sexual coercion, 17.9% (n = 60) experienced rape, and 7.2% (n = 24) experienced both. As number of sexual partners increased, instances of verbal sexual coercion increased for women low in relational sexual assertiveness but not for women high in relational sexual assertiveness. A similar relationship was not found for rape. Among women who experienced both verbal sexual coercion and rape, increases in number of partners in the context of low refusal and relational assertiveness were associated with increases in verbal sexual coercion and rape. Findings suggest sexual assertiveness is related to fewer experiences of sexual coercion.

The quinuclidine PHA-0568487(1) is an agonist of the alpha 7 nicotinic acetylcholine receptor that was designed to mitigate the bioactivation associated with the core scaffold and subsequently remove associated liabilities with in vivo tolerability. The drug metabolites of 1 in nonclinical species were identified in plasma and urine of rats, dogs and monkeys receiving oral administrations of 1. The in vitro biotransformation of 1 was subsequently investigated in multiple species employing cryopreserved hepatocytes, hepatic subcellular fractions and recombinantly-expressed human P450 enzymes. In addition, in vitro metabolism of synthetically prepared metabolite precursors were instrumental in the elucidation of several secondary metabolites. The results indicated that the principal biotransformation of 1 was oxidation of the benzo[1,4]dioxane moiety (M8, M10) followed by subsequent oxidation to a range of secondary metabolites (M1-7, M9, M11, M13-15, and M17-18). The carboxylic acids M1 and M2 resulting from the oxidative cleavage of the dioxane ring were the principal metabolites observed in the plasma, urine and hepatocyte incubations across all species (M1 & M2). Quinuclidine oxidation was another pathway of importance, yielding an N-oxide (M12) which was also observed in all species.P450 2D6 and FMO1 catalyze the oxidation of the quinuclidine nitrogen. The N oxidation of the quinuclidine moiety is consistent with previously published accounts of this scaffold's metabolism and, interestingly, may implicate the uncommon quinuclidine moiety as an entity directing the metabolism of this scaffold (e.g., 1) via FMO1 and P450 2D6 oxidation.

The synthesis and structure-activity relationship studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones as antagonists of the human calcium receptor (CaSR) have been recently disclosed [ Didiuk et al. ( 2009 ) Bioorg. Med. Chem. Lett. 19 , 4555 - 4559 ). On the basis of its pharmacology and disposition attributes, (R)-2-(2-hydroxyphenyl)-3-(1-phenylpropan-2-yl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (1) was considered for rapid advancement to first-in-human (FIH) trials to mitigate uncertainty surrounding the pharmacokinetic/pharmacodynamic (PK/PD) predictions for a short-acting bone anabolic agent. During the course of metabolic profiling, however, glutathione (GSH) conjugates of 1 were detected in human liver microsomes in an NADPH-dependent fashion. Characterization of the GSH conjugate structures allowed insight(s) into the bioactivation pathway, which involved CYP3A4-mediated phenol ring oxidation to the catechol, followed by further oxidation to the electrophilic ortho-quinone species. While the reactive metabolite (RM) liability raised concerns around the likelihood of a potential toxicological outcome, a more immediate program goal was establishing confidence in human PK predictions in the FIH study. Furthermore, the availability of a clinical biomarker (serum parathyroid hormone) meant that PD could be assessed side by side with PK, an ideal scenario for a relatively unprecedented pharmacologic target. Consequently, progressing 1 into the clinic was given a high priority, provided the compound demonstrated an adequate safety profile to support FIH studies. Despite forming identical RMs in rat liver microsomes, no clinical or histopathological signs prototypical of target organ toxicity were observed with 1 in in vivo safety assessments in rats. Compound 1 was also devoid of metabolism-based mutagenicity in in vitro (e.g., Salmonella Ames) and in vivo assessments (micronuclei induction in bone marrow) in rats. Likewise, metabolism-based studies (e.g., evaluation of detoxicating routes of clearance and exhaustive PK/PD studies in animals to prospectively predict the likelihood of a low human efficacious dose) were also conducted, which mitigated the risks of idiosyncratic toxicity to a large degree. In parallel, medicinal chemistry efforts were initiated to identify additional compounds with a complementary range of human PK predictions, which would maximize the likelihood of achieving the desired PD effect in the clinic. The back-up strategy also incorporated an overarching goal of reducing/eliminating reactive metabolite formation observed with 1. Herein, the collective findings from our discovery efforts in the CaSR program, which include the incorporation of appropriate derisking steps when dealing with RM issues are summarized.

Synthesis and structure-activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.

The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.

Previous studies have demonstrated the CYP3A4 mediated oxidation of the 5-aminooxindole motif, present in the trifluoromethylpyrimidine class of PYK-2 inhibitors, to a reactive bis-imine species, which can be trapped with glutathione (GSH) in human liver microsomal incubations. The corresponding 5-aminobenzsultam derivatives, which should possess a similar oxidative liability, do not form GSH conjugates in microsomal incubations. In the current study, we conducted a retrospective analysis on representative 5-aminooxindole and 5-aminobenzsultam PYK-2 inhibitors utilizing CYP3A4 molecular docking and quantum chemical calculations to rationalize the bioactivation differences. Our analysis revealed key differences in (a) active site binding and (b) two-electron oxidation rates, which correlate with GSH adduct formation with the two moieties. The value of linear ion/orbitrap mass spectrometry to detect GSH conjugates with greater sensitivity, compared with conventional triple quadrupole mass spectrometry approaches, was also demonstrated in the course of these studies.

Proline-rich tyrosine kinase 2 (PYK2) is a cytoplasmic, non-receptor tyrosine kinase implicated in multiple signaling pathways. It is a negative regulator of osteogenesis and considered a viable drug target for osteoporosis treatment. The high-resolution structures of the human PYK2 kinase domain with different inhibitor complexes establish the conventional bilobal kinase architecture and show the conformational variability of the DFG loop. The basis for the lack of selectivity for the classical kinase inhibitor, PF-431396, within the FAK family is explained by our structural analyses. Importantly, the novel DFG-out conformation with two diarylurea inhibitors (BIRB796, PF-4618433) reveals a distinct subclass of non-receptor tyrosine kinases identifiable by the gatekeeper Met-502 and the unique hinge loop conformation of Leu-504. This is the first example of a leucine residue in the hinge loop that blocks the ATP binding site in the DFG-out conformation. Our structural, biophysical, and pharmacological studies suggest that the unique features of the DFG motif, including Leu-504 hinge-loop variability, can be exploited for the development of selective protein kinase inhibitors.

Prediction of the metabolic sites for new compounds, synthesized or virtual, is important in the rational design of compounds with increased resistance to metabolism. The aim of the present investigation was to use rational design together with MetaSite, an in silico tool for predicting metabolic soft spots, to synthesize compounds that retain their pharmacological effects but are metabolically more stable in the presence of cytochrome P450 (P450) enzymes. The model compound for these studies was the phenethyl amide (1) derivative of the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. Unlike the parent NSAID, 1 is a potent and selective cyclooxygenase-2 (COX-2) inhibitor and nonulcerogenic anti-inflammatory agent in the rat. This pharmacological benefit is offset by the finding that 1 is very unstable in rat and human microsomes because of extensive P4503 A4/2D6-mediated metabolism on the phenethyl group, experimental observations that were accurately predicted by MetaSite. The information was used to design analogs with polar (glycinyl) and/or electron-deficient (fluorophenyl, fluoropyridinyl) amide substituents to reduce metabolism in 1. MetaSite correctly predicted the metabolic shift from oxidation on the amide substituent to O-demethylation for these compounds, whereas rat and human microsomal stability studies and pharmacokinetic assessments in the rat confirmed that the design tactics for improving pharmacokinetic attributes of 1 had worked in our favor. In addition, the fluorophenyl and pyridinyl amide derivatives retained the potent and selective COX-2 inhibition demonstrated with 1. Overall, the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.

The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.

A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.

The presence, level and disease activity relationships of soluble interleukin-2 receptor (sIL-2R) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients are unresolved. We measured CSF immunoreactive myelin basic protein (MBP), a marker of acute myelin damage, and sIL-2R levels in the CSF from 11 patients with active relapsing remitting (RR) MS, five with stable RR MS, eight with chronic progressive (CP) MS, five with other neurologic diseases, and three normal controls. No measurable (less than 100 units/ml) sIL-2R was present in any of the samples. Conversely, MBP levels were elevated in the active RR group compared to the other four groups. These results indicate that, at the sensitivity of assays currently available, levels of CSF sIL-2R do not correlate with the diagnosis or disease activity of MS.

A prospective study of 84 renal graft recipients demonstrated cytomegalovirus (CMV) disease after transplantation in 37% of patients. Reactivation infection was found in 20 of 44 patients (46%) who were seropositive for CMV prior to transplant and primary CMV disease occurred in 11 of 40 (28%) initially seronegative patients. Nearly all cases of primary disease (91%) were associated with symptoms and in these cases CMV was probably acquired via the donated kidneys. Only 35% of the reactivation infections were associated with clinical symptoms. Actuarial life tables indicated that CMV disease did not reduce the length of graft survival. Herpes simplex virus (HSV) infections were diagnosed in 44 (52%) of the patients and included a fatal case of disseminated disease associated with hepatitis.

Murine monoclonal antibodies (MAbs) selective for an idiotope on a monoclonal antibody (IgG1/kappa) to human myelin basic protein (MBP) peptide 80-89 were prepared by immunization with a synthetic decapeptide specified by RNA that is complementary to the mRNA for human MBP peptide 80-89. The monoclonal anti-idiotypic antibody (anti-ID) reacted with the MAb to human MBP peptide 80-89 but not with a MAb to bovine MBP peptide 79-88 or to murine myeloma IgG1. The reaction between the monoclonal anti-ID and the MAb to the human MBP peptide 80-89 could be inhibited by human MBP peptide 80-89 and to a more limited degree with human MBP peptide 76-85 and bovine MBP peptide 79-88, but not by human MBP peptides 69-81 and 85-96. Practically, the use of a complementary peptide for stimulating an anti-ID response permits a more selective and feasible method for preparing anti-ID reagents. Theoretically, these results provide further support for the molecular basis of the network hypothesis.