Nitrogen heterocycles are among the most significant structural components of pharmaceuticals. Analysis of our database of U.S. FDA approved drugs reveals that 59% of unique small-molecule drugs contain a nitrogen heterocycle. In this review we report on the top 25 most commonly utilized nitrogen heterocycles found in pharmaceuticals. The main part of our analysis is divided into seven sections: (1) three- and four-membered heterocycles, (2) five-, (3) six-, and (4) seven- and eight-membered heterocycles, as well as (5) fused, (6) bridged bicyclic, and (7) macrocyclic nitrogen heterocycles. Each section reveals the top nitrogen heterocyclic structures and their relative impact for that ring type. For the most commonly used nitrogen heterocycles, we report detailed substitution patterns, highlight common architectural cores, and discuss unusual or rare structures.

Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals

Protons dictate the charge and structure of macromolecules and are used as energy currency by eukaryotic cells. The unique function of individual organelles therefore depends on the establishment and stringent maintenance of a distinct pH. This, in turn, requires a means to sense the prevailing pH and to respond to deviations from the norm with effective mechanisms to transport, produce or consume proton equivalents. A dynamic, finely tuned balance between proton-extruding and proton-importing processes underlies pH homeostasis not only in the cytosol, but in other cellular compartments as well.

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Sensors and regulators of intracellular pH

Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157-165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV.

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Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

Covalent drugs have proved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This review surveys the prevalence and pharmacological advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.

The resurgence of covalent drugs

The gastric H,K-ATPase is the primary target for the treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pKa of about 4.0, which allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pKa of about 1.0. PPIs are acid-activated prodrugs that convert to sulfenic acids or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. Because of covalent binding, their inhibitory effects last much longer than their plasma half-life. However, the short half-life of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. PPIs with longer half-life promise to improve acid suppression. All PPIs give excellent healing of peptic ulcers and produce good results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori.

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Pharmacology of proton pump inhibitors

Proton pump inhibitors inhibit the gastric H+/K+-ATPase via covalent binding to cysteine residues of the proton pump. All proton pump inhibitors must undergo acid accumulation in the parietal cell through protonation, followed by activation mediated by a second protonation at the active secretory canaliculus of the parietal cell. The relative ease with which these steps occur with different proton pump inhibitors underlies differences in their rates of activation, which in turn influence the location of covalent binding and the stability of inhibition. Slow activation is associated with binding to a cysteine residue involved in proton transport that is located deep in the membrane. However, this is inaccessible to the endogenous reducing agents responsible for restoring H+/K+-ATPase activity, favouring a longer duration of gastric acid inhibition. Pantoprazole and tenatoprazole, a novel proton pump inhibitor which has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, are activated more slowly than other proton pump inhibitors but their inhibition is resistant to reversal. In addition, tenatoprazole has a greatly extended plasma half-life in comparison with all other proton pump inhibitors. The chemical and pharmacological characteristics of tenatoprazole give it theoretical advantages over benzimidazole-based proton pump inhibitors that should translate into improved acid control, particularly during the night.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2006.02943.x

Review article: the clinical pharmacology of proton pump inhibitors.

Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H(+), K(+)-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.

Pharmacokinetics and pharmacodynamics of the proton pump inhibitors.

Proton pump inhibitors (PPIs), drugs that are widely used for treatment of acid related diseases, are either substituted pyridylmethylsulfinyl benzimidazole or imidazopyridine derivatives. They are all prodrugs that inhibit the acid-secreting gastric (H(+), K(+))-ATPase by acid activation to reactive thiophiles that form disulfide bonds with one or more cysteines accessible from the exoplasmic surface of the enzyme. This unique acid-catalysis mechanism had been ascribed to the nucleophilicity of the pyridine ring. However, the data obtained here show that their conversion to the reactive cationic thiophilic sulfenic acid or sulfenamide depends mainly not on pyridine protonation but on a second protonation of the imidazole component that increases the electrophilicity of the C-2 position on the imidazole. This protonation results in reaction of the C-2 with the unprotonated fraction of the pyridine ring to form the reactive derivatives. The relevant PPI pK(a)'s were determined by UV spectroscopy of the benzimidazole or imidazopyridine sulfinylmethyl moieties at different medium pH. Synthesis of a relatively acid stable analogue, N(1)-methyl lansoprazole, (6b), allowed direct determination of both pK(a) values of this intact PPI allowing calculation of the two pK(a) values for all the PPIs. These values predict their relative acid stability and thus the rate of reaction with cysteines of the active proton pump at the pH of the secreting parietal cell. The PPI accumulates in the secretory canaliculus of the parietal cell due to pyridine protonation then binds to the pump and is activated by the second protonation on the surface of the protein to allow disulfide formation.

Chemistry of covalent inhibition of the gastric (H+, K+)-ATPase by proton pump inhibitors.

The gastric H,K-ATPase, a member of the P2-type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven N-linked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E1 (ion site in) to an E2 (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E2P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E2P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E1 configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.

Jai Moo Shin

Papers

Pharmacology of proton pump inhibitors

Review article: the clinical pharmacology of proton pump inhibitors.

Pharmacokinetics and pharmacodynamics of the proton pump inhibitors.

Chemistry of covalent inhibition of the gastric (H+, K+)-ATPase by proton pump inhibitors.

The gastric HK-ATPase: structure, function, and inhibition