Martin James Wythes

Design of selective, ATP-competitive inhibitors of Akt.

This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.

Synthesis of enantiomerically pure protected β-aryl alanines

Abstract The organozinc reagent (1), prepared from the β-iodoalanine derivative (2), reacts with aryl iodides at 50 °C in the presence of catalytic bis(tri-o-tolylphosphine)palladium dichloride to give in moderate to good yields enantiomerically pure protected S-β-aryl alanine derivatives (4).

The in vivo pharmacological profile of a 5‐HT1 receptor agonist, CP‐122, 288, a selective inhibitor of neurogenic inflammation

1 The aim of the present study was to investigate the in vivo pharmacological profile of CP‐122, 288, an indole‐derivative with a conformationally restricted N‐methylpyrrolidinyl basic side chain in the C‐3 position. This C‐3 substituent structurally differentiates CP‐122, 288 from the 5‐HT1D receptor agonist sumatriptan, which possesses an N, N‐dimethylaminoethyl group. 2 When administered prior to electrical stimulation of the trigeminal ganglion, CP‐122, 288 (0.3–300 ng kg−1, i.v.) produced a dose‐related inhibition of plasma protein extravasation in rat dura mater (minimum effective dose, MED, 3 ng kg−1 i.v., P < 0.05; maximal inhibition of plasma extravasation at 30 ng kg−1 i.v., P < 0.01). Sumatriptan produced a similar inhibition of plasma leakage in the dura, but at much higher dose levels (MED, 100 μg kg−1 i.v., P < 0.05). Thus, CP‐122, 288 is of the order of 104 fold more potent than sumatripan. 3 At all doses tested, CP‐122, 288 did not inhibit plasma protein extravasation measured in extracranial tissues such as the lower lip, eyelid, and conjunctiva. 4 In a separate series of studies in the anaesthetized rat, CP‐122, 288 (0.003‐3 μg kg−1 i.v.) produced no change in either heart rate or mean arterial blood pressure, thus demonstrating that doses of CP‐122, 288 which inhibit plasma protein leakage in rat dura, are devoid of haemodynamic effects. 5 Following a 5 min period of electrical stimulation of the trigeminal ganglion, a 20 min period of sustained neurogenically‐driven plasma extravasation, occurring in the absence of electrical stimulation, was initiated. By administration of the compound 5 min after completing the phase of electrical stimulation, this protocol permitted the evaluation of the activity of CP‐122, 288 on an ongoing and established inflammatory event. CP‐122, 288 (30 and 300 ng kg−1, i.v., P < 0.01 and P < 0.05, respectively) produced a complete inhibition of plasma protein leakage which was consistent with its effects when administered prior to trigeminal ganglion stimulation. 6 In the anaesthetized dog, CP‐122, 288 and sumatriptan, at 1–300 μg kg−1, i.v., produced a dose‐dependent reduction in carotid arterial blood flow and coronary arterial diameter. These data demonstrate that sumatriptan inhibits neurogenic inflammation in the rat (MED, 100 μg kg−1, i.v.), and produces vasoconstriction in the dog, over a similar dose‐range. Interestingly, doses of CP‐122, 288 that inhibit neurogenic inflammation in rat dura mater (0.3–300 ng kg−1) were demonstrated to be devoid of vasoconstrictor activity in either the carotid or coronary vascular beds of dog. 7 These data demonstrate that in the rat, CP‐122, 288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissues, at doses which are devoid of vasoconstrictor activity in dog. Potentially, CP‐122, 288 may be of use for the acute treatment of migraine, without the risk of cardiovascular side‐effects.

A new direct method for the synthesis of enantiomerically pure protected α-amino acids

The organozinc reagent (2), prepared from the protected β-iodo alanine derivative (3) using ultrasonic activation, is efficiently acylated using acid chlorides in the presence of (Ph3P)2PdCl2 to give high yields of enantiomerically pure protected γ-keto α-amino acids (4).

AN IMPROVED SYNTHESIS OF THE UNIQUE ANTI-MIGRAINE AGENT CP-122,288 : A BROMINE ATOM PASSENGER IN AN INTRAMOLECULAR HECK REACTION

Abstract Utilizing a 2,6-dibromoaniline ( 6b ) in place of the original monobromo aniline in the indole forming intramolecular Heck reaction allows for a greater than two-fold improvement in the overall yield of CP-122,288. The second bromine is carried through unmolested, forming a 7-bromoindole analog of CP-122,288 ( 1b ). This result might represent a novel approach to 7-substituted indole derivatives.

Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide.

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.

Reduction of 4-oxo α-amino acids as a route to 4-hydroxylated α-amino acids. Concise approaches to the synthesis of clavalanine, erythro-4-hydroxyornithine and (+)-bulgecinine

The stereochemical course of reduction of derivatives of 4-oxo α-amino acids 3 to give cis- and trans-γ-substituted α-aminobutano-4-lactones 9 and 10 using a range of hydride reducing agents is reported. Although reduction with sodium boranuide (sodium borohydride) in protic solvents proceeds with low stereoselectivity, use of triethylsilane–boron trifluoride–diethyl ether gives good selectivity in favour of the cis-isomer, provided that the 4-substituent is phenyl. Moderate to excellent stereoselectivity in favour of the trans-isomer may be obtained by using L-Selectride® in tetrahydrofuran. The presence of an additional stereogenic centre at C-5 completely overwhelms the effect of the α-centre. Applications of this method in approaches to the synthesis of clavalanine, erythro-4-hydroxyornithine and (+)-bulgecinine are described.

Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.

Stereoselective syntheses of protected D-threonine and L-allo-threonine

Abstract Syntheses of both protected D -threonine and L - allo -threonine are described, in which reagent controlled stereoselective epoxidation of a common intermediate is the key step.

Control of diastereoselectivity in the nucleophilic epoxidation of 1-arylthro-1-nitroalkenes: synthesis of diastereoisomerically pure γ-hydroxy threonine derivatives

Epoxidation of the 1-nitro-1-(p-tolylthio)alkene 1 derived from D-isopropylideneglyceraldehyde with lithium tert-butyl peroxide affords the syn epoxide 2 with moderate selectivity, whereas epoxidation with potassium tert-butyl peroxide affords the anti diastereoisomer 3 preferentially; treatment of each of the epoxides 2 and 3 with amines, including ammonia, gives diastereoisomerically pure α-amino thioesters with no trace of stereoisomeric contamination.