Neladenoson Bialanate Hydrochloride: A Prodrug of a Partial Adenosine†A1 Receptor Agonist for the Chronic Treatment of Heart Diseases.

Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosine A1 receptors (A1 Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1 R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1 R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1 R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1 R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.

Chronic therapy with a partial adenosine A1-receptor agonist improves left ventricular function and remodeling in dogs with advanced heart failure.

BACKGROUND: Adenosine elicits cardioprotection through A1-receptor activation. Therapy with adenosine A1-receptor agonists, however, is limited by undesirable actions of full agonism, such as bradycardia. This study examined the effects of capadenoson (CAP), a partial adenosine A1-receptor agonist, on left ventricular (LV) function and remodeling in dogs with heart failure. METHODS AND RESULTS: Twelve dogs with microembolization-induced heart failure were randomized to 12 weeks oral therapy with CAP (7.5 mg BID; n=6) or to no therapy (control; n=6). LV end-diastolic and end-systolic volumes, ejection fraction, plasma norepinephrine, and n-terminal pro-brain natriuretic peptide were measured before (pre) and 1 and 12 weeks after therapy (post). LV tissue obtained at post was used to assess volume fraction of interstitial fibrosis, sarcoplasmic reticulum calcium ATPase-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, end-diastolic and end-systolic volumes increased and ejection fraction decreased significantly from pre to post (ejection fraction, 30±2 versus 27±1%; P<0.05). In CAP-treated dogs, end-diastolic volume was unchanged; ejection fraction increased significantly after 1 week (36±2 versus 27±2%; P<0.05) with a further increase at post (39±2%; P<0.05), whereas end-systolic volume decreased. CAP significantly decreased volume fraction of interstitial fibrosis, normalized sarcoplasmic reticulum calcium ATPase-2a activity and expression of UCP-2 and UCP-3, and GLUT-1 and GLUT-2 and significantly decreased plasma norepinephrine and n-terminal pro-brain natriuretic peptide. CONCLUSIONS: In heart failure dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial adenosine A1-receptor agonists for the treatment of chronic heart failure.

Total synthesis and structural elucidation of azaspiracid-1. Construction of key building blocks for originally proposed structure.

Syntheses of the three key building blocks (65, 98, and 100) required for the total synthesis of the proposed structure of azaspiracid-1 (1a) are described. Key steps include a TMSOTf-induced ring-closing cascade to form the ABC rings of tetracycle 65, a neodymium-catalyzed internal aminal formation for the construction of intermediate 98, and a Nozaki-Hiyama-Kishi coupling to assemble the required carbon chain of fragment 100. The synthesized fragments, obtained stereoselectively in both their enantiomeric forms, were expected to allow for the construction of all four stereoisomers proposed as possible structures of azaspiracid-1 (1a-d), thus allowing the determination of both the relative and absolute stereochemistry of the natural product.

Stereoselective synthesis of (+/-)-rocaglaol analogues.

An intramolecular hydroxy epoxide opening was used to access the cyclopenta[b]benzofuran ring system of the natural product rocaglaol (2). Our route allowed the stereocontrolled preparation of the rocaglaol derivative (+/-)-(1S*,3S*,3aR*,8bS*)-3b. The synthesis of the (+/-)-(3R*)-epimer of 3b was also achieved. Our strategy is well-suited for the production of analogues with variation of the western ring. [reaction: see text]