Asymptotically Safe Standard Model via Vectorlike Fermions.

We construct asymptotically safe extensions of the standard model by adding gauged vectorlike fermions. Using large number-of-flavor techniques we argue that all gauge couplings, including the hypercharge and, under certain conditions, the Higgs coupling, can achieve an interacting ultraviolet fixed point.

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance.

Decoding the X(5568) as a Fully Open-Flavor sub[over ¯]d[over ¯] Tetraquark State.

We investigate the recent evidence for a charged X(5568) meson as an exotic open-flavor tetraquark state sub[over ¯]d[over ¯] with J^{P}=0^{+}/1^{+} in the framework of QCD sum rules. We use the color antisymmetric [3[over ¯]_{c}]_{su}⊗[3_{c}]_{b[over ¯]d[over ¯]} tetraquark currents in both scalar and axial-vector channels to perform evaluations and numerical analyses. Our results imply that the X(5568) can be interpreted as both the scalar sub[over ¯]d[over ¯] tetraquark state and the axial-vector one, which are in good agreement with the experimental measurement.

Towards Exotic Hidden-Charm Pentaquarks in QCD.

Inspired by P(c)(4380) and P(c)(4450) recently observed by LHCb, a QCD sum rule investigation is performed, by which they can be identified as exotic hidden-charm pentaquarks composed of an anticharmed meson and a charmed baryon. Our results suggest that P(c)(4380) and P(c)(4450) have quantum numbers J(P)=3/2(-) and 5/2(+), respectively. Furthermore, two extra hidden-charm pentaqurks with configurations D̅Σ(c)(*) and D̅(*)Σ(c)(*) are predicted, which have spin-parity quantum numbers J(P)=3/2(-) and J(P)=5/2(+), respectively.

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.

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.

Viable dark matter via radiative symmetry breaking in a scalar singlet Higgs portal extension of the standard model.

We consider the generation of dark matter mass via radiative electroweak symmetry breaking in an extension of the conformal standard model containing a singlet scalar field with a Higgs portal interaction. Generating the mass from a sequential process of radiative electroweak symmetry breaking followed by a conventional Higgs mechanism can account for less than 35% of the cosmological dark matter abundance for dark matter mass M(s)>80 GeV. However, in a dynamical approach where both Higgs and scalar singlet masses are generated via radiative electroweak symmetry breaking, we obtain much higher levels of dark matter abundance.

Is radiative electroweak symmetry breaking consistent with a 125 GeV Higgs mass?

The mechanism of radiative electroweak symmetry breaking occurs through loop corrections, and unlike conventional symmetry breaking where the Higgs mass is a parameter, the radiatively generated Higgs mass is dynamically predicted. Padé approximations and an averaging method are developed to extend the Higgs mass predictions in radiative electroweak symmetry breaking from five- to nine-loop order in the scalar sector of the standard model, resulting in an upper bound on the Higgs mass of 141 GeV. The mass predictions are well described by a geometric series behavior, converging to an asymptotic Higgs mass of 124 GeV consistent with the recent ATLAS and CMS Collaborations observations.

Discovery of pyrrolidine-based β-secretase inhibitors: lead advancement through conformational design for maintenance of ligand binding efficiency.

We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold.

Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement.

A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.

BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteres.

A series of beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a psi(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.

Conformationally biased P3 amide replacements of beta-secretase inhibitors.

We have synthesized and evaluated a series of conformationally biased P3 amide replacements based on an isophthalamide lead structure. The studies resulted in the identification of the beta-secretase inhibitor 7m which has an in vitro IC(50)=35 nM. The synthesis and biological activities of these compounds are described.

Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1).

We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit the production of the secreted amino terminal fragment of an artificial amyloid precursor protein in cell culture. In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases.

Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases.

A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor.

Radiative electroweak symmetry breaking revisited.

In the absence of a tree-level scalar-field mass, renormalization-group methods permit the explicit summation of leading-logarithm contributions to all orders of the perturbative series within the effective potential for SU(2)xU(1) electroweak symmetry. This improvement of the effective potential function is seen to reduce residual dependence on the renormalization mass scale. The all-orders summation of leading-logarithm terms involving the dominant three couplings contributing to radiative corrections is suggestive of a potential characterized by a plausible Higgs boson mass of 216 GeV.

In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists.