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DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of

The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.

P450 enzymes are of great interest for drug metabolism and as potential biocatalysts. Like most P450s, purified CYP3A4 is normally handled and stored in solution because lyophilization greatly reduces its activity. We show here that colyophilization of this enzyme with sucrose or trehalose, but not mannitol, crown ethers or cyclodextrins, allow recovery of full enzymatic activity after rehydration. Sorbitol was almost as efficient, with 85% retention of the original activity. We also show that similar protection is observed through colyophilization of CYP2D6 with trehalose. This procedure should greatly facilitate handling, storage, or use of these enzymes in anhydrous media.

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.

The impact on patients' attitudes of quality report cards on infection control in hospitals has never previously been studied. In 2006, the French government implemented a mandatory report card on infection control activity (ICALIN) in all hospitals. This approach was aimed at encouraging professionals to change their routine practices in case they should lose patients due to a low ICALIN score. Our objective was to assess what impact ICALIN could have on patients' attitude as regards hospital choice. We performed a survey of patients and visitors in 14 randomly selected hospitals of various ICALIN scores. A convenience sample of 381 patients and visitors completed an anonymous questionnaire on ICALIN, their reasons for choosing a hospital and attitude in the event of a low ICALIN score. Factors associated with interest in ICALIN and impact of ICALIN on hospital choice were assessed by logistic regression. Our results showed that 77% of participants were interested in ICALIN. ICALIN was ranked sixth as a reason for choosing a hospital. In the case of a low ICALIN, 24.1% of participants would refuse admission and 54.9% would seek advice from their general practitioner. Sociodemographic factors had no influence on patients' attitude. In conclusion, our survey suggests that patients take note of poor performance on infection control report cards. As most patients rely on their general practitioner to interpret these report cards, there is a definite need for further communication with general practitioners on this issue.

P450 enzymes have attracted the attention of chemists for decades because of their impressive ability to catalyze the hydroxylation of inactivated C--H bonds. However, their use for synthesis in aqueous systems is limited. We report here a survey of the activity of purified human CYP3A4 in the presence of organic solvents or ionic liquids. We show that CYP3A4 tolerates only small amounts (15 %) of water-miscible organic cosolvents or ionic liquids before its activity toward testosterone drops below detection. [BMIM][PF(6)] in a biphasic system was less detrimental to enzyme activity, with 20 % of the activity remaining in the presence of 15 % of this ionic liquid. CYP3A4 activity in the absence of buffer was onlyor=10 % in solvents of the alkane series, with a minimum of 0.85 % water, and with the addition of sucrose and testosterone before enzyme lyophilization. Biphasic solvent systems were more promising, with approximately 85 % of the activity retained.