Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

Natural products: a continuing source of novel drug leads.

Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.

The evolving role of natural products in drug discovery

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

Practical methodologies for the synthesis of indoles.

A series of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines was prepared by standard methodology. These compounds were tested in vitro as antagonists of the binding of [125I]cholecystokinin (CCK) to rat pancreas and guinea pig brain receptors and of the binding of [125I]gastrin to guinea pig gastric glands. All compounds proved to have greater affinity for the peripheral CCK receptor with some analogues having IC50's in the subnanomolar range. In vivo activity of selected compounds in mice is presented and the structure/activity profile of this class of benzodiazepines as CCK antagonists is discussed.

Cholecystokinin Antagonists. Synthesis and Biological Evaluation of 4-Substituted 4H-(1,2,4)Triazolo(4,3-a)(1,4)benzodiazepines.

Addition of Grignard reagents to chiral tert-butyl sulfinimines derived from pyridine 2-carboxaldehyde affords protected 2-pyridyl amines in high yields and diastereoselectivities. The sense of chiral induction is opposite to that predicted via a chelation-controlled transition state.

Reversal of Diastereoselection in the Addition of Grignard Reagents to Chiral 2-Pyridyl tert-Butyl (Ellman) Sulfinimines.

http://link.springer.com/content/pdf/10.1007/978-94-010-9066-7_17.pdf

Novel oxytocin antagonists

Chinolinon-pyrazolon-m1-rezeptor-positive allosterische modulatoren

The preparation of pyrazolo[4,3- c ]quinolinones is reported starting from 2-substituted-5-(2-fluorophenyl)-3-oxo-2,4-dihydro-3 H -pyrazol-3-ones. A one-pot protocol, in which condensation with an orthoamide followed by substitution with a primary amine and subsequent S N Ar-cyclization to provide rapid access to 4- and 5-substituted pyrazolo[4,3- c ]quinolinones was developed.

Robert M. DiPardo

Papers

Cholecystokinin Antagonists. Synthesis and Biological Evaluation of 4-Substituted 4H-(1,2,4)Triazolo(4,3-a)(1,4)benzodiazepines.

Reversal of Diastereoselection in the Addition of Grignard Reagents to Chiral 2-Pyridyl tert-Butyl (Ellman) Sulfinimines.

Novel oxytocin antagonists

Chinolinon-pyrazolon-m1-rezeptor-positive allosterische modulatoren

Preparation of 2,4,5‐Trisubstituted Pyrazolo[4,3‐c]quinolin‐3‐ones.