Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.

https://pharmrev.aspetjournals.org/content/pharmrev/53/4/527.full.pdf

International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

In this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states.

Pathophysiology of endothelin in the cardiovascular system

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.12445

The Concise Guide to PHARMACOLOGY 2013/14: G Protein‐Coupled Receptors

Catalyst-free reactions developed during the last decade and the latest developments in this emerging field are summarized with a focus on catalyst-free reactions in-water and on-water. Various named reactions, multi-component reactions and the synthesis of heterocyclic compounds are discussed including the use of various energy input systems such as microwave- and ultrasound irradiation, among others. Organic chemists and the practitioners of this art both in academia and industry hopefully will continue to design benign methodologies for organic synthesis in aqueous media under catalyst-free conditions by using alternative energy inputs based on fundamental principles.

Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis

A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

Discovery of a novel series of orally active non-peptide endothelin-A (ETA) receptor-selective antagonists.

The invention concerns novel renin-inhibitory peptides which are useful for treating renin-associated hypertension, congestive heart failure, hyperaldosteronism, and diseases caused by retroviruses including HTLV-I and -III. Processes for preparing the peptides, compositions containing them, and methods of using them are included. Also included is a diagnostic method which uses the compounds to determine the presence of renin-associated hypertension, or hyperaldosteronism.

Diol-containing renin inhibitors

Les reactions electrophiles de l'oxazol-2-yllithium et la synthese de bis-oxazolyl methanol sont reportees

William C. Patt

Papers

Structure-activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors.

Discovery of a novel series of orally active non-peptide endothelin-A (ETA) receptor-selective antagonists.

Diol-containing renin inhibitors

Reactions of lithiooxazole

N6-bicycloalkyladenosines with unusually high potency and selectivity for the adenosine A1 receptor.