Thomas Subkowski

Design and synthesis of 1,5- and 2,5-substituted tetrahydrobenzazepinones as novel potent and selective integrin α V β 3 antagonists

Abstract The design and synthesis of novel integrin αVβ3 antagonists based on a 1,5- or 2,5-substituted tetrahydrobenzaezpinone core is described. In vitro activity of respective compounds was determined via αVβ3 binding assay, and selected derivatives were submitted to further characterization in functional cellular assays. SAR was obtained by modification of the benzazepinone core, variation of the spacer linking guanidine moiety and core, and modification of the guanidine mimetic. These efforts led to the identification of novel αVβ3 inhibitors displaying potency in the subnanomolar range, selectivity versus αIIbβ3 and functional efficacy in relevant cellular assays. A method for the preparation of enantiomerically pure derivatives was developed, and respective enantiomers evaluated in vitro. Compounds 31 and 37 were assessed for metabolic stability, resorption in the Caco-2 assay and pharmacokinetics.

Synthesis of highly potent and selective hetaryl ureas as integrin αVβ3-Receptor antagonists

Abstract Solid-phase synthesis and SAR of integrin α V β 3 -receptor antagonists containing a urea moiety as non-basic guanidine mimetic are described. The most potent compounds exhibited IC 50 values towards α V β 3 in the nanomolar range and high selectivity versus related integrins like α IIb β 3 . For selected examples efficacy in functional cellular assays is demonstrated.

Synthesis and SAR of N-substituted dibenzazepinone derivatives as novel potent and selective αVβ3 antagonists

Abstract Synthesis and SARs of new integrin α V β 3 antagonists based on an N -substituted dibenzazepinone scaffold are described. Variation of spacer and guanidine mimetic led to potent compounds exhibiting an IC 50 towards α V β 3 in the nanomolar range, high selectivity versus integrin α IIb β 3 and efficacy in functional cellular assays.

Highly potent and selective αVβ3-receptor antagonists: solid-phase synthesis and SAR of 1-substituted 4-amino-1H-pyrimidin-2-ones

Abstract Solid-phase synthesis and SAR of αVβ3-receptor antagonists based on a N1-substituted 4-amino-1H-pyrimidin-2-one scaffold are described. The most potent compounds exhibited IC50 values towards αVβ3 in the nano- to subnanomolar range and high selectivity versus related integrins like αIIbβ3. For selected examples efficacy in functional cellular assays was demonstrated.