Stephen M. Condon

Nanomolar Inhibitors for Two Distinct Biological Target Families from a Single Synthetic Sequence: A Next Step in Combinatorial Library Design?

One common synthetic route creates small-molecule libraries directed toward two functionally distinct target families. The novel structural template 1 can independently display the necessary pharmacophore patterns for inhibition of members of two different biomolecular target families, the matrix metalloproteinases (MMPs) or the phosphodiesterases (PDEs). The incorporation of multiple target family directed design elements into combinatorial library design could help expedite the pharmaceutical lead discovery process. Z=OR (PDE4), H (MMPs).

SYNTHESE VON INHIBITOREN FUR ZWEI FAMILIEN BIOLOGISCHER TARGETS IN EINER SEQUENZ : EIN NACHSTER SCHRITT BEIM AUFBAU KOMBINATORISCHER BIBLIOTHEKEN ?

Uber nureinen Syntheseweg lassen sich Bibliotheken aus niedermolekularen Verbindungen aufbauen, die auf zwei Targetfamilien mit unterschiedlichen Funktionalitaten ausgerichtet sind. Dies wurde anhand der Entdeckung des Strukturtemplats 1 deutlich, das voneinander unabhangige pharmakophore Muster enthalt, uber die Mitglieder aus einer von zwei Targetfamilien, den Matrix-Metalloproteinasen (MMPs) oder den Phosphodiesterasen (PDEs), inhibiert werden konnen. Durch den Einbau von Bausteinen, die gegen mehrere Targets gerichtet sind, in eine Verbindungsbibliothek kann man so moglicherweise das Auffinden pharmazeutischer Leitstrukuren beschleunigen. Z=OR′ (PDE4), H (MMPs).

Analogues of Human Parathyroid Hormone (1–31)NH2: Further Evaluation of the Effect of Conformational Constraint on Biological Activity

A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.