Nicholas John Newcombe

The directed dihydroxylation of allylic alcohols

Abstract The preparation and dihydroxylation of a series of polyenes and cyclic allylic alcohols using the TMEDA/osmium tetroxide mixture is reported. Remarkably, these reagents lead to high levels of regiochemical and stereochemical control as the oxidant hydrogen-bonds to the allylic alcohol group. A mechanistic hypothesis is presented which invokes the formation of a reactive, bidentate complex between osmium tetroxide and TMEDA at low temperatures.

AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC50, 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC50 range, 0.2–1.7 μmol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G2-M, S, and G1 phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38–153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer249/Thr252, for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise. [Mol Cancer Ther 2009;8(7):1856–66]

Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3S)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)

Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.

Discovery of Checkpoint Kinase Inhibitor (S)-5-(3-Fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by Structure-Based Design and Optimization of Thiophenecarboxamide Ureas.

Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.

The synthesis of (+)-pericosine B

The first synthesis of (+)-pericosine B is described: this takes seven steps and proceeds in 10% overall yield. The key step in our work is a hydrogen-bonding controlled contra-steric dihydroxylation reaction using osmium tetroxide and an amine promoter. The absolute stereochemistry of the natural product was deduced from the known absolute stereochemistry of our starting material and moreover, the relative and absolute stereochemistry of our synthetic material was determined unambiguously from an X-ray crystal structure of an advanced intermediate.

Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors.

Checkpoint kinase-1 (Chk1, CHEK1) is a Ser/Thr protein kinase that mediates the cellular response to DNA-damage. A novel class of 2-ureido thiophene carboxamide urea (TCU) Chk1 inhibitors is described. Inhibitors in this chemotype were optimized for cellular potency and selectivity over Cdk1.

Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

Imidazoles: Sar and Development of a Potent Class of Cyclin-Dependent Kinase Inhibitors.

An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.

Scope of the directed dihydroxylation: application to cyclic homoallylic alcohols and trihaloacetamides

The synthesis and directed dihydroxylation of a range of cyclic alkenes was investigated. Both homoallylic alcohols and homoallylic trihaloacetamides were found to be efficient directing groups, giving rise to good to excellent levels of remote asymmetric induction with OsO4-TMEDA. Interestingly, in all cases examined, trifluoroacetamides were found to be superior to trichloroacetamides as directing groups and an argument is presented which rationalises this observation.

Rapid synthesis of high-loading resins using triple branched protected monomer for dendrimer synthesis

Resins with loading up to 96 nmol/bead were prepared by solid-phase dendrimerisation using a symmetrical 1→3 C-branched isocyanate monomer.