BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign.

Cardiac output improvement by pecavaptan: a novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure.

Aims: Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short-term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long-term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre-clinical HF models.

Vascular Protection and Decongestion Without Renin-Angiotensin-Aldosterone System Stimulation Mediated by a Novel Dual-Acting Vasopressin V1a/V2 Receptor Antagonist.

Increased plasma vasopressin levels have been shown to be associated with the progression of congestive heart failure. Vasopressin mediates water retention by renal tubular V2 receptor activation as well as vasoconstriction, cardiac hypertrophy, and fibrosis through V1a receptor activation. Therefore, we developed a novel, dual-acting vasopressin receptor antagonist, BAY 1753011, with almost identical Ki-values of 0.

Synthesis of the louisianin alkaloid family via a 1,2,4-triazine inverse-electron-demand Diels-Alder approach.

Isolated in 1995, the four members of the louisianin family (A, B, C and D) are simple pyridine and 2-pyridone alkaloids that display both antibacterial and anticancer activity. Herein we describe the synthesis of all four members of the louisianin family, from a conveniently prepared 1,2,4-triazine and via a common tetrasubstituted pyridine intermediate. This study includes the synthesis of louisianin B in both racemic form and as the (-)-enantiomer.

Intramolecular Stetter cyclisation of Morita-Baylis-Hillman adducts: a versatile approach towards bicycloenediones.

Bicyclic enediones of various sizes can be efficiently assembled by intramolecular Stetter cyclisation of readily available Morita-Baylis-Hillman adducts.