Alan B. Cooper

Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase

An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity.

Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.

Brutons tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

Pyrazolo[1,5-a]pyrimidine-based inhibitors of HCV polymerase.

The present paper describes a novel series of HCV RNA polymerase inhibitors based on a pyrazolo[1,5-a]pyrimidine scaffold bearing hydrophobic groups and an acidic functionality. Several compounds were optimized to low nanomolar potencies in a biochemical RdRp assay. SAR trends clearly reveal a stringent preference for a cyclohexyl group as one of the hydrophobes, and improved activities for carboxylic acid derivatives.

Discovery of 4H-pyrazolo[1,5-a]pyrimidin-7-ones as potent inhibitors of hepatitis C virus polymerase

A series of 4H-pyrazolo[1,5-a]pyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited potent activity in enzymatic assay. The synthesis and structure-activity relationship are also described.

Chapter 12. Recent Advances in Antifungal Agents

Publisher Summary This chapter discusses the recent advances in antifungal agents. Reviews on pharmacokinetics, mechanism of action, activity, and clinical application of liposomal encapsulated amphotericin B (L-AMB) have appeared. A report on the treatment of fungal infections in heart transplant recipients, using L-AMB has also appeared. Synergy between AMB and rifampin has been demonstrated in vitro and possibly in vivo . The success of ketoconazole, the first broad-spectrum orally efficacious azole, stimulated the search for better agents in this class of antifungals. A mini review of azoles with emphasis on the newer triazole types has appeared. The unique mechanism of action of the allylamines has attracted much attention to these potent antifungal agents. The activity of antifungals of moropholines class has been attributed to the accumulation of abnormal sterols. Two excellent reviews on the cell envelope and nutrient transport in C. albicans have appeared. Chitin synthetase inhibition continues to be a viable approach for the design of antifungal agents. Another class of antifungal agents under investigation is beta-glucan synthesis inhibitors. Pradimycin A, isolated from a new strain of Actinomadura hibisca , exhibited broad-spectrum fungicidal activity, including activity against many strains that have been resistant to other antifungal agents. The in vivo efficacy of pradimycin A against a variety of Candida sp has been compared with 5-FC, a number of azoles, and AMB. Fumifungin, isolated from an A. fumigatus sp., has showed in vitro activity against yeasts and filamentous fungi. A considerable degree of information with a minimal amount of compound and effort may encourage other laboratories to adopt this new procedure.

Synthesis of (±)-8-methyl cercosporamide : stereochemical correlation of natural (-)-cercosporamide with (±)-usnic acid

Abstract The absolute configuration of the antifungal antibiotic cercosporamide was established as C-9b-(−)-(S) by correlation with synthetic (+)-8-methylcercosporamide. This was accomplished via conversion of the isoxazole (6) available from (+)-usnic acid. Structure revision of the key isoxazole (6), previously assigned structure (5), is described; some of the 13C-assignments for usnic acid made by previous workers have also been corrected.

Discovery of C-imidazole azaheptapyridine FPT inhibitors.

The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.

TOTAL SYNTHESIS OF THE ANTIFUNGAL CYCLIC DEPSIPEPTIDES SCH 57697 AND AUREOBASIDIN A

Abstract A novel cyclic depsinonapeptide antifungal 1a (Sch 57697) and its isomer 1b were synthesized by a fragment coupling approach and this methodology was applied to the total synthesis of the natural product aureobasidin A. Synthetic strategies for coupling of N-methyl amino acids with minimal racemization are discussed. Biological evaluation of isomers 1a and 1b demonstrated the importance of chirality at the β-hydroxy-N-methylvaline (OHMeVal) position.

A convenient degradation of polyoxin D to uracil polyoxin C: access to key intermediates and synthesis of antifungal α-aminoacyl derivatives of UPOC

Abstract A convenient degradation of readily available polyoxin D under Edman conditions gave carboxyuracil polyoxin C 3 in high yield. Decarboxylation to uracil polyoxin C 5 (UPOC) and ring contraction to imidazolone compound 8 , gav important nikkomycin Z and X intermediates respectively. Syntheses of new polyoxin/nikkomycin analogs 12 – 27 , some with excellent chitin synthetase inhibition and Candida albicans whole cell activity are described. The importance of β-methyl substituted amino acid side chains for whole cell activity is highlighted.

Synthesis of 14-α-aminomethyl substituted lanosterol derivatives; inhibitors of fungal ergosterol biosynthesis

Several 14-α-aminomethyl-substituted lanosterol derivatives have been synthesized involving a complete Δ7,8to Δ8,9isomerization; these compounds are inhibitors of fungal ergosterol biosynthesis and are active against intact Candida and dermatophyte strains.