Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors.

Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.

A hydrogen borrowing annulation strategy for the stereocontrolled synthesis of saturated aza-heterocycles.

An iridium catalyzed method for the synthesis of saturated aza-heterocycles from amines and diols is reported. A wide range of substituted heterocycles can be obtained using this approach including products bearing substituents at the C2, C3 and C4 positions. Employing water as the solvent, enantiopure diols could undergo annulation with minimal racemization, enabling the synthesis of valuable enantioenriched C3 and C4-substituted saturated aza-heterocycles.

Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor.

The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).

Discovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis.

PKCθ plays an important role in T cell biology and is a validated target for a number of disease states. A series of potent and selective PKCθ inhibitors were designed and synthesized starting from a HTS hit compound. Cell activity, while initially a challenge to achieve, was built into the series by transforming the nitrile unit of the scaffold into a primary amine, the latter predicted to form a new hydrogen bond to Asp508 near the entrance of the ATP binding site of PKCθ. Significant improvements in physiochemical parameters were observed on introduction of an oxetane group proximal to a primary amine leading to compound 22, which demonstrated a reduction of symptoms in a mouse model of multiple sclerosis.

Intramolecular hetero Diels-Alder (Povarov) approach to the synthesis of the alkaloids luotonin A and camptothecin.

[reaction: see text] Pyrrolo[3,4-b]quinolines can be formed through the coupling of anilines with N-propargylic substituted heterocyclic aldehydes in the presence of mild Lewis acid catalysts (Ln(OTf)3). The coupling proceeds through sequential imine formation and a formal intramolecular aza-Diels-Alder (Povarov) reaction. This approach was applied in a total synthesis of luotonin A and a formal synthesis of camptothecin.

Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases.

Protein kinase C θ (PKCθ) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that while antiviral responses are PKCθ-independent, T cell responses associated with autoimmune diseases are PKCθ-dependent. Thus, potent and selective inhibition of PKCθ is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKCθ inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKCδ were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE).

Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors.

Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.

Multicomponent reactions involving 2-methyleneaziridines: rapid synthesis of 1,3-disubstituted propanones.

Ring opening of 1-alkyl-2-methyleneaziridines 1 or 2 is accomplished with organocopper reagents (R(2)CuLi or RMgX/CuI) in the presence of boron trifluoride diethyl etherate giving 1-substituted propan-2-ones 3-9 in 42-88% yield. Ring opening with RMgCl/CuI in the absence of the Lewis acid allows further alkylation of the metalloenamine (metalated imine) intermediate in a regiocontrolled manner. The sequential formation of two new intermolecular carbon-carbon bonds in this reaction provides a rapid entry into a variety of 1,3-disubstituted propan-2-ones, including 11 and 14-23. The scope and mechanism of this multicomponent reaction (MCR) has been assessed. It is established that this MCR tolerates alkyl, aryl, and benzylic Grignard reagents and a wide range of electrophiles, including alkyl iodides, bromides, and tosylates, as well as epoxides and aldehydes. In addition, gem-dimethyl substitution on the exocyclic double bond of the 2-methyleneaziridine is tolerated. This MCR has been applied to the one-pot synthesis of (Z)-6-heneicosen-11-one, 25, an important sex attractant of the Tussock moth. Using 3-deuterio-1-(1-phenylethyl)-2-methyleneaziridine, 26, we determined that this MCR occurs predominantly by direct ring opening at the sp(3)-hybridized aziridine carbon atom (C-3).