The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

https://www.physiology.org/doi/pdf/10.1152/physrev.00030.2010

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chemistry and many derivatives are specifically designed to make drug–target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chemical methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chemistry.

Organic carbamates in drug design and medicinal chemistry.

The present invention relates to dihydropyrazole compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

Mitotic kinesin inhibitors

BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

/pdf/bace1-b-secretase-inhibitors-for-the-treatment-of-alzheimer-wpl4jm4dt1.pdf

BACE1 (β-Secretase) Inhibitors for the Treatment of Alzheimer's Disease

β-Secretase (memapsin 2; BACE-1) is the first protease in the processing of amyloid precursor protein leading to the production of amyloid-β (Aβ) in the brain. It is believed that high levels of brain Aβ are responsible for the pathogenesis of Alzheimer's disease (AD). Therefore, β-secretase is a major therapeutic target for the development of inhibitor drugs. During the past decade, steady progress has been made in the evolution of β-secretase inhibitors toward better drug properties. Recent inhibitors are potent, selective and have been shown to penetrate the blood-brain barrier to inhibit Aβ levels in the brains of experimental animals. Moreover, continuous administration of a β-secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A small number of β-secretase inhibitors have also entered early phase clinical trials. These developments offer some optimism for the clinical development of a disease-modifying drug for AD.

/pdf/developing-b-secretase-inhibitors-for-treatment-of-alzheimer-27645x5062.pdf

Developing β-secretase inhibitors for treatment of Alzheimer’s disease

Prodrugs of COX-2 inhibitors are described as being useful in treating inflammation and inflammation-related disorders.

Prodrugs of benzenesulfonamide-containing COX-2 inhibitors

Design of potent inhibitors of human beta-secretase. Part 2.

Compounds of Formula (I), wherein R2, Y6, R6A, R6, and R8 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, synthetic methods, and intermediates are also disclosed.

Pyridino [2 , 3-b] pyrazinones as pde-5 inhibitors

Cette invention concerne des composes, des tautomeres de ces composes, et des sels pharmaceutiquement acceptables de ces composes ou tautomeres. Ces composes possedent une structure representee par la formule (I), dans laquelle R2, X6, Y6, R6 et R8 sont definis dans les pieces descriptives de la demande. Des compositions pharmaceutiques correspondantes, des procedes de traitement, des procedes de synthese et des intermediaires sont egalement divulgues.

Pyridine[3,4-b]pyrazinones

Disclosed are compounds of formula X, which are useful in treating Alzheimer's disease and other similar diseases. Pharmaceutical compositions comprising compounds of formula X and methods of preparing the compounds of formula X are also disclosed.

Brown David L

Papers

Prodrugs of benzenesulfonamide-containing COX-2 inhibitors

Design of potent inhibitors of human beta-secretase. Part 2.

Pyridino [2 , 3-b] pyrazinones as pde-5 inhibitors

Pyridine[3,4-b]pyrazinones

Hydroxy alkyl amines