Michael Czarniecki

Discovery of Cyclic Acylguanidines as Highly Potent and Selective beta-Site Amyloid Cleaving Enzyme (BACE) Inhibitors: Part I-Inhibitor Design and Validation

A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180 degrees in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.

Application of Fragment-Based NMR Screening, X-ray Crystallography, Structure-Based Design, and Focused Chemical Library Design to Identify Novel μM Leads for the Development of nM BACE-1 (β-Site APP Cleaving Enzyme 1) Inhibitors

Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper

Structure-activity relationships of pyrroloquinazolines as thrombin receptor antagonists.

A series of pyrroloquinazolines has been discovered that represent novel small molecule inhibitors of the intramolecular ligand of the thrombin receptor. Analogs were prepared to study the structure-activity relationships of substitution at the N 1, N3, and N7 positions of the heterocycle. Compounds 4e and 4f have been identified with IC50s of 56 and 52 nM, respectively.

Design, synthesis, and structure-activity relationship studies of himbacine derived muscarinic receptor antagonists

A parallel synthesis of racemic himbacine analogs was carried out by N-alkylation of various commercially available cyclic amine derivatives with the alkylating agent 4 which bears the tricyclic unit of himbacine. Several of these analogs have potency comparable to that of himbacine, albeit lacking the desired selectivity. Structure-activity relationship studies support the existence of a hydrophobic pocket in the receptor where the piperidine ring of dihydrohimbacine binds.

Substituted 1,3,5-triazines as cholesteryl ester transfer protein inhibitors

Abstract A series of substituted 1,3,5-triazines (represented by 2 ) were synthesized and evaluated for their cholesteryl ester transfer protein (CETP) inhibitory activities. Among the most potent compounds were those with R = benzyl (IC 50 = 9 μM) and R = [(2-naphthalenyl)methyl] (IC 50 = 5 μM).

Cyclic Hydroxyamidines as Amide Isosteres: Discovery of Oxadiazolines and Oxadiazines as Potent and Highly Efficacious γ-Secretase Modulators in Vivo

Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aβ(42) in various animal models.

Small molecule modulators of toll-like receptors.

The human immune response is mediated through two parallel immune components. The innate immunes system responds to pathogens and abnormal cells through multiple cell types including dendritic cells, macrophages, neutrophils, and natural killer cells and represents a first line of defense in mammals. The adaptive immune response system responds to pathogens and abnormal cells through the T cell and B cell systems, neutralizing the these components with T-cell receptors and antibodies respectively. Tolllike receptor (TLR) functions are activated as part of the innate immune response system recognizing macromolecular molecular components of microorganisms. These structures are the pathogenassociated molecular patterns (PAMPs). Subsequent to activation the innate immune system triggers the production of cytokines and chemokines and induces the adaptive immune system. The action of vaccines is due, in part, to the activation of the TLR system. Originally discovered in fruit flies the TLRs were found as an entire family of receptors in humans. The basic biology and clinical potential of TLR based therapeutics have been extensively and recently reviewed. These reviews provide a broad perspective on TLRs including mechanisms of action, therapies based on novel biologics, and an analysis of ongoing clinical trials. Agonists of the TLRs would be immune system enhancers and have been proposed to be useful in the treatment of cancer and infectious diseases. Antagonists, on the other hand, are thought to have a therapeutic role in suppressing overactive immune responses, as occurs in chronic inflammatory and autoimmune diseases. Eleven TLRs have been identified, 10 of which have been found in humans. Figure 1 illustrates the cellular localization and natural ligand for the 10 human TLRs. TLR2, TLR4, TLR7, TLR8, and TLR9 have been the targets for small molecule drug discovery efforts. This Miniperspective will focus on the medicinal chemistry of small molecule TLR modulators. This is a very new field, and as such, much of the current state of the art is within the published patent filings of both large and small pharmaceutical companies. Reporting of biological activity is complicated by the fact that direct binding assays for the TLR family have not been used and SAR, when it exists, is from a variety of reporter gene or functional cell based assays. The goal of this Miniperspective is to illustrate the small molecule chemotypes that have been identified as TLR modulating agents, analyze when possible the structure-activity relationships, and place this new and emerging field of medicinal chemistry in context.

Inhibitors of PDE1 and PDE5 cGMP phosphodiesterases: patents and therapeutic potential

Cyclic 3′5′-guanosine monophosphate (cGMP) is a key second messenger involved in the processes of intracellular signalling. Steady state levels of cGMP are modulated through a balance between the rates of formation and degradation of the nucleotide. A potential therapeutic approach to manipulation of cGMP is the inhibition of the phosphodiesterases PDE1 and PDE5. PDE5 inhibitors have been targeted by many companies and have resulted in a large number of patents. The disclosed inhibitors cover an eclectic range of polycyclic nitrogen heterocycles. Activities reported show IC50 values in the low nanomolar to subnanomolar range. A wide range of tissue, cellular and in vivo effects are also reported for these PDE5 inhibitors. By contrast, only a very few patents have appeared which claim PDE1 inhibitory activity. The potential use of PDE1 and PDE5 inhibitors in the treatment of coronary artery disease, hypertension, congestive heart failure, erectile dysfunction and pulmonary hypertension is discussed.

An efficient synthesis of Wiedendiol-A from (+)-sclareolide

An efficient synthesis of Wiedendiol-A (1) is described starting from commercially available (+)-sclareolide. This synthesis also confirms the absolute stereochemistry of Wiedendiol-A.

Design and synthesis of phosphinic acids that triply inhibit endothelin converting enzyme, angiotensin converting enzyme and neutral endopeptidase 24.11

Abstract We have synthesized a series of phosphinic acids as inhibitors of a metalloprotease endothelin converting enzyme (ECE). Potent ECE inhibitors 4g and 4o were identified. These compounds are members of a novel class of ECE inhibitors that are also potent inhibitors of angiotensin converting enzyme and neutral endopeptidase.