Search

Efforts to develop an HIV-1 vaccine include those focusing on conserved structural elements as the target of broadly neutralizing monoclonal antibodies. MAb D5 binds to a highly conserved hydrophobic pocket on the gp41 N-heptad repeat (NHR) coiled coil and neutralizes through prevention of viral fusion and entry. Assessment of 17-mer and 36-mer NHR peptides presenting the D5 epitope in rodent immunogenicity studies showed that the longer peptide elicited higher titers of neutralizing antibodies, suggesting that neutralizing epitopes outside of the D5 pocket may exist. Although the magnitude and breadth of neutralization elicited by NHR-targeting antigens are lower than that observed for antibodies directed to other epitopes on the envelope glycoprotein complex, it has been shown that NHR-directed antibodies are potentiated in TZM-bl cells containing the FcγRI receptor. Herein, we report the design and evaluation of covalently stabilized trimeric 51-mer peptides encompassing the complete gp41 NHR. We demonstrate that these peptide trimers function as effective antiviral entry inhibitors and retain the ability to present the D5 epitope. We further demonstrate in rodent and nonhuman primate immunization studies that our 51-mer constructs elicit a broader repertoire of neutralizing antibody and improved cross-clade neutralization of primary HIV-1 isolates relative to 17-mer and 36-mer NHR peptides in A3R5 and FcγR1-enhanced TZM-bl assays. These results demonstrate that sensitive neutralization assays can be used for structural enhancement of moderately potent neutralizing epitopes. Finally, we present expanded trimeric peptide designs which include unique low-molecular-weight scaffolds that provide versatility in our immunogen presentation strategy. [ABSTRACT FROM AUTHOR]

Stark spectroscopy is used to study the variation of electronic properties with the size of helical H-aggregates. The unique and important property of these aggregates is that their size is controlled by the properties of the DNA template.

The first catalytic, enantioselective syntheses of quinine and quinidine is described. Asymmetric catalyst-based synthesis opens the possibility of accessing diastereomeric products with the help of a common route.

Thiourea catalysis is applied to the Pictet-Spengler-type cyclization of hydroxylactams, thus affording highly enantioenriched indolizidinones and quinolizidinones. Asymmetric catalysis via anion-binding mechanisms is applicable for a wide variety of valuable transformations involving highly reactive cationic intermediates.

Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX 2 R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX 2 R, culminating in lead compound PE-6 . PE-6 displays sub-nanomolar binding affinity and functional potency on OX 2 R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX 1 R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class. [ABSTRACT FROM AUTHOR]

Chromatography is routinely used in drug discovery as a means to isolate intermediates and final compounds. From a sustainability perspective, it is one of the largest contributors of solvent waste in the drug discovery process. The medicinal chemistry subgroup within the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective aimed at providing chemists with practical tools and easily implemented techniques to improve the sustainability of drug discovery through reduction of the waste generated during chromatography. This perspective also offers alternatives to traditional, silica gel-based chromatography as well as information on how to avoid chromatography completely through use of crystallization and reaction telescoping. [ABSTRACT FROM AUTHOR]

The synthesis of THPP-1 (VI) is given. [ABSTRACT FROM AUTHOR]

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits sub-nanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cGMP and pGluR1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant elevation of mRNA encoding substance P (Sub P) and enkephalin (ENK) after MK-8189 administration. The PDE10A tracer [ 3 H]MK-8193 was used determine the PDE10A enzyme occupancy (EO) required for efficacy in behavioral models. In the rat conditioned avoidance responding assay, MK-8189 significantly decreased avoidance behavior at PDE10A EO greater than ~48%. MK-8189 significantly reversed an MK-801-induced deficit in pre-pulse inhibition at PDE10A EO of ~47% and higher. Target engagement of MK-8189 in rhesus monkeys was examined with [ 11 C]MK-8193 in PET studies and plasma concentrations of 127nM MK-8189 yielded ~50% EO in the striatum. The impact of MK-8189 on cognitive symptoms was evaluated using the objective retrieval task in rhesus monkeys. MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ~29% PDE10A EO. These findings demonstrate the robust impact of MK-8189 on striatal signaling and efficacy in preclinical models of symptoms associated with schizophrenia. Data from these studies were used to establish the relationship between preclinical efficacy, plasma exposures, and PDE10A EO to guide dose selection of MK-8189 in clinical studies. Significance Statement We describe the primary pharmacology of MK-8189 a PDE10A inhibitor under evaluation for the treatment of schizophrenia. We report efficacy in preclinical models that have been used to characterize other PDE10A inhibitors and atypical antipsychotics. The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.)

Acinetobacter baumannii , a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.

Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity. Herpesviruses share a conserved DNA polymerase, the inhibition of which is validated as an effective strategy to disrupt viral replication. By utilizing a non-nucleoside inhibitor of the viral DNA polymerase, we sought to develop agents covering multiple herpesviruses (e.g., CMV, VZV, HSV1/2, EBV, and HHV6). Herein is described the invention of an oxazolidinone class of broad-spectrum non-nucleoside herpes antiviral inhibitors. A lead compound ( 42 ) with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV infection., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Efforts to develop an HIV-1 vaccine include those focusing on conserved structural elements as the target of broadly neutralizing monoclonal antibodies. MAb D5 binds to a highly conserved hydrophobic pocket on the gp41 N-heptad repeat (NHR) coiled coil and neutralizes through prevention of viral fusion and entry. Assessment of 17-mer and 36-mer NHR peptides presenting the D5 epitope in rodent immunogenicity studies showed that the longer peptide elicited higher titers of neutralizing antibodies, suggesting that neutralizing epitopes outside of the D5 pocket may exist. Although the magnitude and breadth of neutralization elicited by NHR-targeting antigens are lower than that observed for antibodies directed to other epitopes on the envelope glycoprotein complex, it has been shown that NHR-directed antibodies are potentiated in TZM-bl cells containing the FcγRI receptor. Herein, we report the design and evaluation of covalently stabilized trimeric 51-mer peptides encompassing the complete gp41 NHR. We demonstrate that these peptide trimers function as effective antiviral entry inhibitors and retain the ability to present the D5 epitope. We further demonstrate in rodent and nonhuman primate immunization studies that our 51-mer constructs elicit a broader repertoire of neutralizing antibody and improved cross-clade neutralization of primary HIV-1 isolates relative to 17-mer and 36-mer NHR peptides in A3R5 and FcγR1-enhanced TZM-bl assays. These results demonstrate that sensitive neutralization assays can be used for structural enhancement of moderately potent neutralizing epitopes. Finally, we present expanded trimeric peptide designs which include unique low-molecular-weight scaffolds that provide versatility in our immunogen presentation strategy., Competing Interests: Competing interests statement:C.W., I.T.R., P.S.K., D.D.N., M.C., E.A.O., R.W.H., S.B.P., R.H., S.M.S., and J.G.J. were employees of Merck & Co., Inc. at the time when the work was performed, and may own Merck stock exceeding $5,000. The authors disclose a patent application relevant to this study: World Intellectual Property Organization, WO2013142298 A1 2013-09-26.

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.

The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.

A robust and general catalyst system facilitates the alkoxylation of activated heteroaryl halides with primary, secondary, and select tertiary alcohols without the need for an excess of either coupling partner. This catalyst system displays broad functional-group tolerance and excellent regioselectivity, and is insensitive to the order of reagent addition., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The regio- and enantioselective cyclization of pyrroles onto N-acyliminium ions generated in situ from hydroxylactams is reported. Modest to excellent ee's and yields are obtained in these novel Pictet-Spengler-type reactions with a chiral thiourea-pyrrole catalyst. Useful synthetic transformations of the versatile pyrroloindolizidinone and pyrroloquinolizidinone products are presented.