Utilisation en synthese asymetrique d'imidazolidines derivees de diamines chirales possedant un axe de symetrie C_2

SIGLEINIST T 77082 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

The discovery of first-in-class drugs: origins and evolution

Recent analyses claim phenotypic screening to be superior to target-based approaches for drug discovery. However, looking at the etiology and chronology of events that led to the approval of all 106 first-in-class drugs from 1999 to 2012, we realized that the majority of these (73) were discovered through target-based approaches. Of 31 drugs identified in the absence of a target hypothesis only 7 were found using true phenotypic screening. The discovery of the other 24 ‘phenotypic’ drugs occurred through a chemocentric approach where a particular compound with known pharmacology served as the starting point. We also found that the median time from first disclosure of the concept (target, pathway, chemotype) to FDA approval was 25 years for non-target-based and 20 years for target-based drugs. Few of the non-target based drugs had their origin after 1985, the time around which the technologies necessary for target-based approaches were established. We conclude that target-based drug discovery is successful, and recognize that HTS and other innovations applied in the past 25 years have only recently started to have a major impact on new approvals. We further suggest viewing phenotypic screening as a logical evolution of target-based approaches and consider it a novel discipline rather than a neoclassic approach, with all implications

Structure of human cyclophilin A in complex with the novel immunosuppressant sanglifehrin A at 1.6 A resolution.

Sanglifehrin A (SFA) is a novel immunosuppressant isolated from Streptomyces sp. that binds strongly to the human immunophilin cyclophilin A (CypA). SFA exerts its immunosuppressive activity through a mode of action different from that of all other known immunophilin-binding substances, namely cyclosporine A (CsA), FK506, and rapamycin. We have determined the crystal structure of human CypA in complex with SFA at 1.6 A resolution. The high resolution of the structure revealed the absolute configuration at all 17 chiral centers of SFA as well as the details of the CypA/SFA interactions. In particular, it was shown that the 22-membered macrocycle of SFA is deeply embedded in the same binding site as CsA and forms six direct hydrogen bonds with CypA. The effector domain of SFA, on the other hand, has a chemical and three-dimensional structure very different from CsA, already strongly suggesting different immunosuppressive mechanisms. Furthermore, two CypA.SFA complexes form a dimer in the crystal as well as in solution as shown by light scattering and size exclusion chromatography experiments. This observation raises the possibility that the dimer of CypA.SFA complexes is the molecular species mediating the immunosuppressive effect

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

Direct Renin Inhibitors as A New Therapy for Hypertension

Perspective Articel - No abstract require