Potent and selective oxindole-based vasopressin 1b receptor antagonists with improved pharmacokinetic properties.

Herein we report the discovery of a novel series of vasopressin 1b (V1b) receptor antagonists, starting from potent but metabolically labile oxindole SSR149415. Masking the proline N,N-dimethyl amide moiety as an oxazole and attaching a benzylic amine moiety to the northern phenyl ring resulted in potent and selective V1b receptor antagonists with improved metabolic stability and improved pharmacokinetic properties in rat. Compound 18c was found to be efficacious in a rat model of anti-depressant activity.

Discovery and SAR of 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.

We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.

An offline-addition format for identifying GPCR modulators by screening 384-well mixed compounds in the FLIPR.

Although fluorescence imaging plate reader (FLIPR)-based assays have been widely used in high-throughput screening, improved efficiencies in throughput and fidelity continue to be investigated. This study presents an offline compound addition protocol coupled with a testing strategy using mixtures of compounds in a 384-well format to identify antagonists of the neurokinin-1 receptor expressed in the human astrocytoma cell line (U373 MG). Substance P evoked a concentration-dependent increase in intracellular cellular Ca(2+) with an EC(50) value of 0.30 +/- 0.17 nM, which was inhibited by neurokinin-1 (NK1) antagonists L-733,060 and L-703,606. Test compounds, as mixtures of 10 compounds/well, were added to the cells offline using an automated dispensing unit and incubated prior to performing the assay in the FLIPR. Using the offline protocol, a higher through put of ~200,000 compounds was achieved in an 8-h working day, and several novel structural classes of compounds were identified as antagonists for the NK1 receptor. These studies demonstrate that the offline compound addition format using a mixture of compounds in a 384-well FLIPR assay provides an efficient platform for screening and identifying modulators for G-protein-coupled receptors.

Synthesis and SAR of highly potent and selective dopamine D(3)-receptor antagonists: 1H-pyrimidin-2-one derivatives.

The synthesis and SAR of novel highly potent and selective dopamine D(3)-receptor antagonists based on a 1H-pyrimidin-2-one scaffold are described. A-690344 antagonized PD 128907-induced huddling deficits in rat (ED(50) 6.1mg/kg po), a social interaction paradigm.

Synthesis and SAR of highly potent and selective dopamine D(3)-receptor antagonists: Quinolin(di)one and benzazepin(di)one derivatives. herve.geneste@abbott.com.

The synthesis and SAR of novel and selective dopamine D(3)-receptor antagonists based on a 3,4-dihydro-1H-quinolin-2-one, a 1,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1H-quinoline-2,4-dione or a 3,4-dihydro-1H-benzo[b]azepine-2,5-dione scaffold are discussed. A706149 (2.15mg/kg, po) antagonizes PD 128907-induced huddling deficits in rat, a social interaction paradigm.

Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: variations on the 1H-pyrimidin-2-one theme.

In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.