Alzheimer’s disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.

We have developed a series of potent and selective factor VIIa inhibitors based on the 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid scaffold. These amidine-containing compounds have low oral bioavailability. Herein, we describe our efforts to improve the oral bioavailability of the parent amidine via a prodrug strategy where the amidine basicity and polarity were reduced with either an alkoxy-amidine or a carbamate prodrug.

Structure-activity relationships and binding mode of novel heterocyclic factor VIIa inhibitors will be described. In these inhibitors, a highly basic 5-amidinoindole moiety has been successfully replaced with a less basic 5-aminopyrrolo[3,2-b]pyridine scaffold.

Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.

La presente invention concerne de nouveaux inhibiteurs des facteurs VIIa, IXa, Xa, XIa, en particulier du facteur VIIa, representes par la formule (I), des compositions pharmaceutiques contenant ces inhibiteurs et des methodes comprenant l'utilisation de ces inhibiteurs pour le traitement ou la prevention des troubles thrombo-emboliques. L'invention concerne egalement des procedes permettant de preparer ces inhibiteurs.

The auricle or pinna is subject to a large number of diseases. Those where surgery is the treatment of choice or those with an appearance mimicking a surgically amendable condition will be the focus of this article. Acquired problems only will be considered. Congenital conditions are not within our scope. Acquired surgically responsive lesions of the auricle can be divided into sun-induced and traumatic, with the bulk being neoplastic lesions initiated by ultraviolet radiation. The epidermis and dermis are thin with a variably thick, generally thin, subcutaneous layer separating the dermis from the perichondrium. Lymphatic drainage of the pinnal is made to the superficial parotid, retroauricular, and superficial cervical lymph nodes. The thinness of the skin backed by the relatively tumor-resistant elastic cartilage can affect both the clinical presentation and clinical behavior of some of the malignant neoplasms. but changes significantly in the organ transplant population (2.43 in kidney, 1.1:l in heart).4 Ultraviolet B radiation is the principal etiologic agent for both BCC and SCC, with the fairest skin being at the greatest risk.5