Charles K. Marlowe

Solid phase organic synthesis (SPOS): A novel route to diketopiperazines and diketomorpholines

SummaryThe solid phase synthesis of libraries containing a 1,3,4,6-tetrasubstituted-2,5-diketo-1,4-piperazine scaffold (DKP) or a 3,4,6-trisubstituted-2,5-diketo-1,4-morpholme scaffold (DKM) from α-bromocarboxylic acids and amines is described. Using a design strategy which we refer to as divergent library design, both templates were prepared from a common intermediate. The general utility of this synthetic route in creating novel, non-peptidyl chemical libraries is discussed.

Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: structures based on the (D)-Arg-Gly-Arg tripeptide sequence.

A series of arginine aldehyde inhibitors was designed as transition state (TS) analogues based on the known factor Xa specific substrate Cbz-D-Arg-Gly-Arg-pNA. BnSO2-(D)Arg-Gly-Arg-H (20) was found to be the most potent and selective inhibitor of factor Xa and prothrombinase activity in this series.

Peptide cyclization on TFA labile resin using the trimethylsilyl (TMSE) ester as an orthogonal protecting group

Abstract The trimethylsilylethyl ester group was used as an orthogonal protecting group to perform an on-resin cyclization of a peptide prepared by conventional Fmoc protection strategy. Fmoc-Asp(OTMSE)OH was prepared, incorporated into a peptide, deprotected in the presence of fluoride, cyclized in the presence of BOP, and cleaved from the resin to afford directly a head-to-sidechain cyclic peptide.

Design and synthesis of glycolic and mandelic acid derivatives as factor Xa inhibitors

A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration.

A short asymmetric synthesis of N-α-fmoc-N-δ-boc-α-methyl-D-ornithine

Abstract The title compound was synthesized in six steps from N -Cbz-L-alanine through asymmetric alkylation of a cis -2-phenyl-4-methyl-5-oxazolidinone with tert -butyl 4-iodobutyrate. The cis -2-phenyl-4-methyl-5-oxazolidinone was obtained via a new BF 3 •Et 2 O mediated condensation with benzaldehyde dimethyl acetal and N -Cbz-L-alanine. The δ-carboxylate was converted to the δ - N -Boc derivative 5 through a Curtius rearrangement. Hydrogenation yielded N - δ -Bod-α-methyl-D-ornithine 6 , which was protected as the α - N -Fmoc derivative for incorporation into solid phase peptide synthesis.

Discovery of Transition State Factor Xa Inhibitors as Potential Anticoagulant Agents

Factor Xa is an attractive biological target in the discovery and development of either parenteral or orally active anticoagulant agents. Several strategies have been utilized at COR Therapeutics in the pursuit of tri-peptide based transition state mimetic factor Xa inhibitors with high aqueous solubility. Some of these inhibitors have displayed excellent in vitro potency in inhibiting factor Xa in the prothrombinase complex. More importantly, these compounds showed strong in vivo antithrombotic efficacy without significant bleeding complications in several animal thrombosis models. These results demonstrated that small molecule factor Xa inhibitors could be advantageous over Warfarin and LMWH. For the discovery and development of orally active anticoagulant agents, small organic molecules as reversible factor Xa inhibitors were explored. From a medicinal chemistry perspective, significant insight has been gained regarding the in vivo antithrombotic efficacy and pharmacokinetic behaviors of each class of factor Xa inhibitors. This review will focus on the design and discovery of transition state factor Xa inhibitors as potential parenteral anticoagulant agents. Several excellent comprehensive review articles on factor Xa inhibitors have appeared recently [1-4].