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During development of the residual solvent method using headspace-GC for a drug substance, an unexpected peak was observed in the chromatography. GC–MS analysis confirmed the unknown peak identity as isobutylene. An understanding of the source of the isobutylene was required in order to develop appropriate impurity and residual solvent control strategies for the drug substance. The experiments performed to determine the source of the isobutylene peak observed in the headspace-GC chromatography and how the tert-butoxycarbonyl (BOC) de-protection step used in the drug substance synthesis contributes to its observation are discussed.

This article describes the development and optimization of chemical reactions and subsequent preparation of the API LY503430 under cGMPs to fund first human dose (FHD) clinical evaluation as a potential therapeutic agent for Parkinson's disease. Reasons and rationale are presented for changes in solvents and reagents. One of the major developments presented here is the replacement of a chiral chromatography with a diastereomeric salt resolution. This article also discusses a preferred orientation issue with LY503430 which complicated the XRPD analysis.

Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (-) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.

A total synthesis of lipid I (4), a membrane-associated intermediate in the bacterial cell wall (peptidoglycan) biosynthesis pathway, is reported. This highly convergent synthesis will enable further studies on bacterial resistance mechanisms and may provide insight toward the development of new chemotherapeutic agents with novel modes of action.

Serine hydroxymethyltransferase (SHMT) derived from recombinant E. coli was found to be able to catalyze the condensation between glycine and 4-pentenaldehyde, affording enantiopure l -erythro-2-amino-3-hydroxy-6-heptenoic acid (AHHA) in high yield and throughput. Conversion of this chiral intermediate of biosynthetic origin to the oral carbacephalosporin antibiotic loracarbef (Lorabid®) via β-lactam forming reactions and subsequent Dieckmann cyclization was achieved.

The title compound was synthesized via 1,3-dipolar cycloaddition of diazoacetonitrile and diethyl fumarate.

A total synthesis of lipid I (4), a membrane-associated intermediate in the bacterial cell wall (peptidoglycan) biosynthesis pathway, is reported. This highly convergent synthesis will enable further studies on bacterial resistance mechanisms and may provide insight toward the development of new chemotherapeutic agents with novel modes of action.

Bacterial peptidoglycan is composed of a network of beta-[1,4]-linked glyan strands that are cross-linked through pendant peptide chains. The final product, the murein sacculus, is a single, covalently closed macromolecule that precisely defines the size and shape of the bacterial cell. The recent increase in bacterial resistance to cell wall active agents has led to a resurgence of activity directed toward improving our understanding of the resistance mechanisms at the molecular level. The biosynthetic enzymes and their natural substrates can be invaluable tools in this endeavor. While modern experimental techniques have led to isolation and purification of the biosynthetic enzymes utilized in peptidoglycan biosynthesis, securing useful quantities of their requisite substrates from natural substrates has remained problematic. In an effort to address this issue, we report the first total synthesis of lipid II (4), the final monomeric intermediate utilized by Gram positive bacteria for peptidoglycan biosynthesis.

A series of diarylsulfonylureas with exceptionally broad-spectrum activity against syngeneic rodent solid tumors in vivo is described. Their discovery resulted from a program dedicated to in vivo screening for novel oncolytics in solid tumor models, rather than traditional ascites leukemia models. The structures, oral efficacy, side-effect profile, and mechanism of action of these sulfonylureas appear to be distinct from previously known classes of oncolytics. An extensive series of analogues was prepared to probe structure-activity relationships (SAR), with particular focus on the substituent patterns of each aryl domain. Quantitative analysis of these substituent SARs, using the method of cluster significance analysis, showed the lipophilicity of the substituents to be the dominant determinant of activity. One compound from the series, LY186641 (104, sulofenur), has progressed to Phase I clinical trials as an antitumor drug.

The stereospecific synthesis of the PPAR alpha/gamma agonist I was accomplished via ethylation of the optically pure tribydroxy derivative 6, itself derived via an enzymatic resolution. The ethylation can be accomplished without epimerization only under strict control of the reaction conditions and the choice of base (sodium tert-amylate), temperature (-30 degrees C), order of addition, and solvent (DMF). The key diastereospecific S(N)2 reaction of the phenol 4 with S-2-chloropropionic acid is best achieved via the sodium phenoxide of 4 derived from Na-0 as the reagent of choice. The structure elucidation and key purification protocols to achieve pharmaceutical purity will also be described.

2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC(50) = 22.6 nM).

Bacterial peptidoglycan is composed of a network of beta-[1,4]-linked glyan strands that are cross-linked through pendant peptide chains. The final product, the murein sacculus, is a single, covalently closed macromolecule that precisely defines the size and shape of the bacterial cell. The recent increase in bacterial resistance to cell wall active agents has led to a resurgence of activity directed toward improving our understanding of the resistance mechanisms at the molecular level. The biosynthetic enzymes and their natural substrates can be invaluable tools in this endeavor. While modern experimental techniques have led to isolation and purification of the biosynthetic enzymes utilized in peptidoglycan biosynthesis, securing useful quantities of their requisite substrates from natural substrates has remained problematic. In an effort to address this issue, we report the first total synthesis of lipid II (4), the final monomeric intermediate utilized by Gram positive bacteria for peptidoglycan biosynthesis.

The title compound was synthesized via 1,3-dipolar cycloaddition of diazoacetonitrile and diethyl fumarate.

The title compound was synthesized in a regiocontrolled way from 5-cyano-1H-pyrazole-4-carboxylic acid, ethyl ester (5) with isobutylene, p-toluenesulfonic acid and methylamine.