Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability.

Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer's Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.

Mitigating the Metabolic Liability of Carbonyl Reduction: Novel Calpain Inhibitors with P1' Extension.

Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1H)-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored in vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability against carbonyl reduction. These efforts led to the identification of P1' modified calpain inhibitors with significantly improved pharmacokinetic profile including P1' N-methoxyamide 23 as potential candidate compound for non-central nervous system indications.

Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer's Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides.

Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.

Oxazole-based peptide macrocycles: a new class of G-quadruplex binding ligands.

Herein we report on the synthesis and DNA binding properties of a new class of water soluble oxazole-based peptide macrocycles that bind selectively to quadruplex DNA, with no detectable binding to duplex DNA. We have recently identified one quadruplex in the proto-oncogene c-kit that is suspected to act as a regulatory element for the expression of the c-kit gene. Here we provide the first example of a ligand binding to and stabilizing the c-kit quadruplex. Moreover, we show that these macrocycles show a preference for the c-kit quadruplex as compared to the human telomeric quadruplex.

One-pot homolytic aromatic substitutions/HWE olefinations under microwave conditions for the formation of a small oxindole library.

[reaction: see text] An efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Horner-Wadsworth-Emmons olefination for the preparation of a small library of alpha,beta-unsaturated oxindoles is presented. Microwave-induced heating is used to conduct these reactions. The homolytic aromatic substitution is mediated by the persistent radical effect.

Intermolecular radical addition and addition/cyclization reactions of alkoxyamines onto nonactivated alkenes.

[reaction: see text] Alkoxyamines A, which are readily prepared from commercially available starting materials, undergo efficient thermal radical carboaminoxylations onto various nonactivated alkenes to provide 1,4-functionalized malonates B in good to excellent yields. The experiments are very easy to conduct. The carboaminoxylations can be combined with radical cyclization and fragmentation processes.

Synthesis of a deca-lithium cage containing an [(RN)2As(mu-NR)As(NR)2]4- tetraanion; a homologue of group 15 trianions of the type [E(NR)3]3-.

The novel, deca-lithium cage [(mtaNHLi)(As2(Nmta)5)-Li(4).2thf]2 (1) (mtaN = 5-methylthiazolyl, C4H4N2S) contains an imido-bridged tetraanion [(mtaN)2As(mu-Nmta)-As(Nmta)2]4-, which represents a new type of multi-functional imido group 15 ligand framework (homologous with group 15 anions of the type [As(NR)3]3-).