Enabling New Targets by Integrated Lead Discovery

Advances in biomedical science and technology are directing attention to drug targets that were previously deemed difficult or even "un-druggable". At Novartis, we have re-designed our approach to lead discovery to exploit these opportunities. Placing biological understanding of disease at the center of lead discovery strategies, we make extensive use of focussed screening in complex biologically relevant models. We emphasize methods that build confidence also in hits with weak activity and build on synergies between different technologies to answer key scientific questions in projects. Here we describe the scientific, cultural and organizational changes that had to be implemented to introduce this concept of "Integrated Lead Discovery"

Organofluorine compounds. Part XIII. The halide-promoted fragmentation of 1-chloro-1-fluoro-2-(a-silylaklyl)cyclopropanes: a new entry to fluorodienes

When heated in the presence of Bu4N+.X- (X = F, Cl), 1-chloro-1-fluoro-2-(trimethylsilyl)methylcyclopropanes I (R = H, Me; R1 = Me, Et) undergo smooth ring-opening fragmentation to give 2-fluorobutadienes RCH:CFCR1:CH2 with high yields. Despite unfavorable geometries, the reaction is concerted and the inversion mode of rotation dominates over the retention mode by a factor of roughly 100. [on SciFinder (R)

The ylide route to fluorodienes

Ylides Ph3P+C-RR1 (R = H, Me; R1 = OMe, Cl, Me, Pr, Ph, CO2Me) underwent Wittig reaction with fluoroalkenals MeCR2:CFCHO (R2 = H, Me) to give 52-95% MeCR2:CFCH:CRR1. This reaction occurred at approx. the same rate, and gave nearly the same Z-E mixts., as the corresponding nonfluorinated aldehydes. [on SciFinder (R)

Derivation of Rapamycin: Adventures in Natural Product Chemistry

The macrolide rapamycin was first described as an antifungal agent in 1975. It attracted our interest in the early 90s based on its reported immunosuppressive activity in transplantation models and based on indications that its mechanism of action was different from those of the known immunosuppressive agents ciclosporin and FK506, although the biological target and the molecular details were yet to be discovered. In this review we describe our efforts to chemically modify this complex and chemically very sensitive natural product. Despite the limitations regarding the reaction conditions compatible with rapamycin we discovered ways of selectively modifying specific functional groups. This allowed us, among others, to improve the stability of the parent molecule towards ring-opening. Our efforts culminated in the discovery and development of the 40-O-alkylated derivative everolimus which became a useful drug in solid organ transplantation, in various cancer indications and as the active principle of the market leading drug-eluting stent

The Diels-Alder approach to musk odor type arenes

The readily accessible 2-halogeno-1-trimethylsilyloxy-1,3-butadienes, e.g. CH2:CRCR1:CHOSiMe3 (R = H, Me; R1 = F, Cl) react smoothly with MeO2CC.tplbond.CCO2Me to afford 4-halophthalic esters, e.g. I. I (R = H, R1 = Fl) was subsequently converted into the isobenzofuran analog II of phantolide like musk fragrances by Grignard methylation, cyclization, and acetylation. [on SciFinder (R)