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In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.

4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.

Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.

A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.

Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.

The isolation and characterization of embryonic and adult stem cells from higher-order mammalian species will enhance the understanding of the biology and therapeutic application of stem cells. The aim of this study was to purify rhesus mesenchymal stem cells (MSCs) from adult bone marrow and to characterize functionally their abilities to differentiate along diverse lineages. Adherent cells from adult rhesus macaque bone marrow were characterized for their growth characteristics, lineage differentiation, cell-surface antigen expression, telomere length, chromosome content, and transcription factor gene expression. Rhesus bone marrow MSCs (BMSCs) are very heterogeneous, composed of primarily long, thin cells and some smaller, round cells. The cells are capable of differentiating along osteogenic, chondrogenic, and adipogenic lineages in vitro. The cell morphology and multipotential differentiation capabilities are maintained throughout extended culture. They express CD59, CD90 (Thy-1), CD105, and HLA-1 and were negative for hematopoietic markers such as CD3, CD4, CD8, CD11b, CD13, CD34, and platelet endothelial cell adhesion molecule-1 (CD31). BMSCs were also demonstrated to express the mRNA for important stem cell-related transcription factors such as Oct-4, Sox-2, Rex-1, and Nanog. Rhesus BMSCs have a normal chromosome content, and the shortening of telomeres is minimal during early passages. These data demonstrate that BMSCs isolated from rhesus macaques have a high degree of commonality with MSCs isolated from other species. Therefore, isolation of these cells provides an effective and convenient method for rapid expansion of pluripotent rhesus MSCs.

For 18 years we have analysed several parameters directly or indirectly involved in immunologic functions in 713 children (age: 0-14 years) suffering from CNSRD (frequently relapsing bronchitis, chronic bronchitis, frequently relapsing or chronic obstructive bronchitis, asthma bronchiale, cystic fibrosis). In all 6,067 data were evaluated. The estimation of the immunoglobulins (in serum and secretions) and the serum level of alpha-1-antitrypsin (alpha-1-AT) had the highest relevance for diagnosis and prognosis of CNSRD. Immunodeficiencies were detected in form of humoral antibody deficiency syndromes as well as local secretory IgA deficiency (MALT insufficiency). The results suggest that the MALT-insufficiency during early childhood is a high risk factor for the development of CNSRD, especially of obstructive lung diseases. In chronic bronchitis the mean levels of serum-IgA were significantly increased (p less than 0.001) and reactively increased serum mean levels of IgM and/or IgG were observed in some chronic bronchitis forms but not during the whole childhood. In homocygote and heterocygote defective alpha-1-AT types the prognosis of chronic lung disease (chronic obstructive bronchitis and/or bronchial asthma) was especially poor. Despite BCG vaccination in the neonatal period most children had negative tuberculin skin tests. This suggests that also the cellular immunofunctions may be depressed in children with CNSRD. Blood group, isoagglutinins, Zn and Fe serum levels had only limited importance for diagnosis and prognosis of the CNSRD. We recommend the estimation of these parameters in special cases only.