Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A1 receptor antagonists and their biological evaluation.

Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.

Is Vertical Transmission of SARS-CoV-2 Infection Possible in Preterm Triplet Pregnancy? A Case Series.

There is limited data regarding the vertical transmission (VT) of severe acute respiratory syndrome-coronavirus-2 infection. We report the first case of VT in preterm triplet pregnancy, with all triplets positive for severe acute respiratory syndrome-coronavirus-2 at 20 hours and day 5 of life. This report reiterates the need for an expedited formulation of a simple, standardized, and reproducible international case definition and classification for VT.

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate.

The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.

A2B adenosine receptor antagonists: Design, synthesis and biological evaluation of novel xanthine derivatives.

A2BAdoR 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 A2BAdoR antagonists have been reported in literature, however most of the compounds suffer from poor pharmacokinetic profile. Therefore, with the aim to identify novel, potent and selective A2BAdoR antagonists with improved pharmacokinetic properties, we first explored more constrained form of MRS-1754 (4). To improve the metabolic stability, several linker modifications were attempted as replacement of amide linker along with different phenyl or other heteroaryls between C8 position of xanthine head group and terminal phenyl ring. SAR optimization resulted in identification of two novel A2BAdoR antagonists, 8-{1-[5-Oxo-1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-xanthine (31) and 8-(1-{2-Oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-1H-pyrazol-4-yl)-1,3-dipropyl-xanthine (65), with high binding affinity (Ki = 1 and 1.5 nM, respectively) and selectivity for A2BAdoR with very good functional potency of 0.9 nM and 4 nM, respectively. Compound 31 and 65 also displayed good pharmacokinetic properties in mice with 27% and 65% oral bioavailability respectively. When evaluated in in vivo mice model of asthma, compound 65 also inhibited airway inflammation and airway reactivity in ovalbumin induced allergic asthma at 3 mpk dose.

Design and synthesis of novel xanthine derivatives as potent and selective A2B adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases.

Adenosine induces bronchial hyperresponsiveness and inflammation in asthmatics through activation of A2B adenosine receptor (A2BAdoR). 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 A2BAdoR antagonist may be beneficial for the potential treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). Towards this effort, we explored several prop-2-ynylated C8-aryl or heteroaryl substitutions on xanthine chemotype and found that 1-prop-2-ynyl-1H-pyrazol-4-yl moiety was better tolerated at the C8 position. Compound 59, exhibited binding affinity (Ki) of 62 nM but was non-selective for A2BAdoR over other AdoRs. Incorporation of substituted phenyl on the terminal acetylene increased the binding affinity (Ki) significantly to <10 nM. Various substitutions on terminal phenyl group and different alkyl substitutions on N-1 and N-3 were explored to improve the potency, selectivity for A2BAdoR and the solubility. In general, compounds with meta-substituted phenyl provided better selectivity for A2BAdoR compared to that of para-substituted analogs. Substitutions such as basic amines like pyrrolidine, piperidine, piperazine or cycloalkyls with polar group were tried on terminal acetylene, keeping in mind the poor solubility of xanthine analogs in general. However, these substitutions led to a decrease in affinity compared to compound 59. Subsequent SAR optimization resulted in identification of compound 46 with high human A2BAdoR affinity (Ki = 13 nM), selectivity against other AdoR subtypes and with good pharmacokinetic properties. It was found to be a potent functional A2BAdoR antagonist with a Ki of 8 nM in cAMP assay in hA2B-HEK293 cells and an IC50 of 107 nM in IL6 assay in NIH-3T3 cells. Docking study was performed to rationalize the observed affinity data. Structure-activity relationship (SAR) studies also led to identification of compound 36 as a potent A2BAdoR antagonist with Ki of 1.8 nM in cAMP assay and good aqueous solubility of 529 µM at neutral pH. Compound 46 was further tested for in vivo efficacy and found to be efficacious in ovalbumin-induced allergic asthma model in mice.

Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression.

Adenosine A2A receptor (A2AAdoR) 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 A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models).

Frequency and intensive care related risk factors of pneumothorax in ventilated neonates.

OBJECTIVES: Relationships of mechanical ventilation to pneumothorax in neonates and care procedures in particular are rarely studied. We aimed to evaluate the relationship of selected ventilator variables and risk events to pneumothorax. METHODS: Pneumothorax was defined as accumulation of air in pleural cavity as confirmed by chest radiograph. Relationship of ventilator mode, selected settings, and risk procedures prior to detection of pneumothorax was studied using matched controls. RESULTS: Of 540 neonates receiving mechanical ventilation, 10 (1.85%) were found to have pneumothorax. Respiratory distress syndrome, meconium aspiration syndrome, and pneumonia were the underlying lung pathology. Pneumothorax mostly (80%) occurred within 48 hours of life. Among ventilated neonates, significantly higher percentage with pneumothorax received mandatory ventilation than controls (70% versus 20%; P < 0.01). Peak inspiratory pressure >20 cm H2O and overventilation were not significantly associated with pneumothorax. More cases than controls underwent care procedures in the preceding 3 hours of pneumothorax event. Mean airway pressure change (P = 0.052) and endotracheal suctioning (P = 0.05) were not significantly associated with pneumothorax. Reintubation (P = 0.003), and bagging (P = 0.015) were significantly associated with pneumothorax. CONCLUSION: Pneumothorax among ventilated neonates occurred at low frequency. Mandatory ventilation and selected care procedures in the preceding 3 hours had significant association.