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A scalable process for the manufacture of a Hsp90 inhibitor was developed and optimized. Key features in the seven-step process include a selective SNAr reaction followed by an Ullmann-type coupling of indazolone to an aryl halide. This improved process afforded 65% yield over two critical steps compared to 25% following the Medicinal Chemistry route.

1. Elaborate studies of cholesteryl ester transfer protein (CETP) polymorphisms and genetic deficiency in humans suggest direct links between CETP, high-density lipoprotein cholesterol (HDL-c) levels and coronary heart diseases. The hypothesis that CETP inhibition by small molecule inhibitors raises HDL-c has been validated clinically with structurally-diverse CETP inhibitors such as torcetrapib, anacetrapib, dalcetrapib and evacetrapib. 2. Despite promising phase 2 results with respect to HDL-c elevation, torcetrapib was discontinued in phase 3 trials due to increased mortality rates in the cardiovascular outcomes study. Emerging evidence for the adverse effects hints at off-target chemotype-specific cardiovascular toxicity, possibly related to the pressor effects of torcetrapib, since structurally diverse CETP inhibitors such as anacetrapib, evacetrapib and dalcetrapib are not associated with blood pressure increases in humans. Nonclinical follow-up studies showed that torcetrapib induces aldosterone biosynthesis and secretion in vivo and in vitro, an effect which is not observed with other CETP inhibitors in clinical development. 3. As part of ongoing efforts to identify novel CETP inhibitors devoid of pressor effects, strategies were implemented towards the design of compounds, which lack the 1,2,3,4-tetrahydroquinoline (THQ) scaffold present in torcetrapib. In this article, we disclose results of structure-activity relationship studies for a series of novel non-THQ CETP inhibitors, which resulted in the identification of a novel isonipecotic acid derivative 10 (also referred to as PF-04445597) with vastly improved oral pharmacokinetic properties mainly as a result of improved aqueous solubility. This feature is attractive in that, it bypasses significant investments needed to develop compatible solubilizing formulation(s) for oral drug delivery of highly lipophilic and poorly soluble compounds; attributes, which are usually associated with small molecule CETP inhibitors. PF-04445597 was also devoid of aldosterone secretion in human H295R adrenal carcinoma cells.

The preparation of Rink-chloride and its utility in attaching various nucleophiles to a solid support are described.

An enantioselective synthesis of chiral hydroxyurea based 5-lipoxygenase inhibitors is reported via a five-step sequence in about 30% overall yield. The synthesis is based on a novel tandem nucleop...

Design and synthesis of some TSA inhibitors on novel molecular frameworks is described. This TSA analog design culminates in the preparation of the phosphonate 18.

A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 and TNF. Two related imidazole classes (B and C) had previously been reported to bind to CSBP and to inhibit LPS-stimulated human monocyte IL-1 and TNF production. The members of the earlier series exhibited varying degrees of potency as inhibitors of the enzymes of arachidonic acid metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkylated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and were found to be weak to inactive as inhibitors of these enzymes. One of the compounds, 9 (SB 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good potency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 significantly reduced edema and increased bone mineral density in this model.

A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.

As part of an effort to define the pharmacophore and discover the mechanism by which the antiinflammatory dual cyclooxygenase / 5-lipoxygenase inhibitors SK&F 86002 and SK&F 105809 inhibit IL-1 biosynthesis, a series of substituted 2,4,5-triarylimidazole derivatives were prepared and evaluated as inhibitors of IL-1 and 5-lipoxygenase biosynthesis.

Racemic hydroxyureas can be efficiently resolved on a preparative scale using (4S)-4-benzyl-2-oxazolidinone-3-carbonyl chloride 3. The resulting carbamates can be separated by chromatography and hydrolysis of these diastereomers yields enantiomerically pure hydroxyureas.

A novel procedure for the preparation of 2,6,9-trisubstituted purine libraries has been developed.

A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.

La synthese stereoselective des antibiotiques du titre se fait via l'oxa-2bicyclo [3.3.1] nonene-6dione-3,4

Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKCα and ERK kinase activity is observed.

La synthese stereoselective des antibiotiques du titre se fait via l'oxa-2bicyclo [3.3.1] nonene-6dione-3,4

Novel methodology for the diastereoselective synthesis of some branched functionalized homoallylic amine derivatives is described. The protocol starts with a 3,6-dihydrothiazine-1-oxide, which is readily obtained in a totally stereospecific manner by the hetero-Diels—Alder cycloaddition of an N-sulfinyl dienophile and a 1,3-diene. Various Grignard reagents have been added to these adducts to afford sulfoxide derivatives which have been manipulated stereoselectively via [2,3]- or [3,3]-sigmatropic rearrangements into branched homoallylic amines potentially useful for further synthetic transformations.

Diels-Alder adducts of dienes and N-sulfinyltoluenesulfonamide can be used in synthesis of homoallylic amine derivatives having predictable stereochemistry and double bond geometry.

Bactobolin (Z), a broad spectrum antibiotic and antitumor agent produced by a Pseudomonas strain, has been synthesized in a completely stereoselective manner in approximately twenty steps from readily available cyclohexenol 2;.

Synthese diastereoselective de derives d'α-hydroxy amines β,γ-insaturees a partir d'un oxyde-1 de dihydro-3,6 thiazine-1,2

Synthese diastereoselective de derives d'α-hydroxy amines β,γ-insaturees a partir d'un oxyde-1 de dihydro-3,6 thiazine-1,2