Emergence of Japanese encephalitis in eastern parts of Madhya Pradesh, India.

Background & Objectives: Emerging zoonotic and vector-borne diseases are posing new challenges to public health authorities. Morbidities and mortalities due to acute encephalitis syndrome (AES) is a serious health problem in paediatric patients. We conducted serological investigations on AES cases from six districts of north eastern Madhya Pradesh (MP), India for Japanese encephalitis (JE).

Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties . Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC.

Discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) and analogs as small molecule Na1.7/ Nav1.8 blockers for the treatment of pain.

The voltage-gated sodium channel Na1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Na1.7 to pain in humans.

Innovating the treatment of COPD exacerbations: a phone interactive telesystem to increase COPD Action Plan adherence.

Introduction: Self-management interventions with Written Action Plans and case management support have been shown to improve outcomes in patients with chronic obstructive pulmonary disease (COPD). Novel telehealth technologies may improve self-management interventions. The objectives of this study were to determine whether the use of an interactive phone telesystem increases Action Plan adherence, improves exacerbation recovery and reduces healthcare use in a real-life practice of a COPD clinic.

Discovery of Potent and Selective A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression.

Adenosine A receptor (AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-]purin-2-one derivatives that displays functional antagonism of the A receptor with a high degree of selectivity over A, A, and A receptors.

Design and synthesis of novel xanthine derivatives as potent and selective A adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases.

Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A adenosine receptor (AAdoR). Selective antagonists have been shown to attenuate airway reactivity and improve inflammatory conditions in pre-clinical studies. Hence, the identification of novel, potent and selective AAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD).

Rational design, synthesis, and structure-activity relationships of 5-amino-1H-pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure-activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A Receptor Antagonists and Their Biological Evaluation.

Our initial structure-activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound 25 as a potent and selective A adenosine receptor (AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability.

A adenosine receptor antagonists: Design, synthesis and biological evaluation of novel xanthine derivatives.

AdoR is a low affinity adenosine receptor that functions by Gs mediated elevation of cAMP and subsequent downstream signaling. The receptor has been implicated in lung inflammatory disorders like COPD and asthma. Several potent and selective AAdoR antagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile.

An evaluation of mass drug administration compliance against filariasis of tikamgarh district of madhya pradesh-a household-based community study.

Background: Mass drug administration (MDA) means once-in-a-year administration of diethyl carbamazine (DEC) tablet to all people (excluding children under 2 years, pregnant women and severely ill persons) in identified endemic areas. It aims at cessation of transmission of lymphatic filariasis.

Objective: To study the coverage and compliance of MDA in Tikamgarh district during the campaign in April 2010.

Gamma interferon release assay for monitoring of treatment response for active tuberculosis: an explosion in the spaghetti factory.

Few studies have correlated the results of interferon (gamma interferon) release assays (IGRAs) with known markers of tuberculosis (TB) treatment response. We report the results of serial QuantiFERON-TB gold in-tube assay (QFT) testing on 149 patients with active tuberculosis and correlate the results with smear and culture conversion. We show that QFT results do not offer much value for treatment monitoring of TB disease.

Discovery of novel and potent heterocyclic carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel heterocyclic carboxylic acid based protein tyrosine phosphatase 1B (PTP1B) inhibitors with hydrophobic tail have been synthesized and characterized. Structure-activity relationship (SAR) optimization resulted in identification of several potent, selective (over the highly homologous T-cell protein tyrosine phosphatase, TCPTP) and metabolically stable PTP1B inhibitors. Compounds 7a, 19a and 19c showed favorable cell permeability and pharmacokinetic properties in mouse with moderate to very good oral (% F=13-70) bio-availability.

Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets.

Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable.

Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction.

The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability.

1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction.

A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity.

Correlation between brain/plasma ratios and efficacy in neuropathic pain models of selective metabotropic glutamate receptor 1 antagonists.

We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification.

Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists.

SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists.

A-412997 is a selective dopamine D4 receptor agonist in rats.

A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide) is a highly selective dopamine D4 receptor agonist that binds with high affinity to rat dopamine D4 and human dopamine D4.4 receptors (Ki=12.1 and 7.

Synthesis of 4,5-diaryl-1H-pyrazole-3-ol derivatives as potential COX-2 inhibitors.

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its analogues 11a-c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the O-alkylated arylbromide intermediate.

Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction.

A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.

Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist.

Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated.

Kiwifruit promotes laxation in the elderly.

Numerous anecdotal reports have suggested that kiwifruit (Actinidia deliciosa) has laxative effects. This could be an acceptable dietary supplement, especially for elderly people who often present with constipation. We wished to obtain objective evidence as to whether or not kiwifruit eaten regularly could promote laxation in elderly people.