Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 () for the treatment of Alzheimer's disease. A key component of the design involved a 2,5--tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work.

Visibility of Board-Certified Dermatologists on TikTok.

Tik Tok is an emerging social media platform that provides a novel opportunity for health practitioners such as dermatologists to disseminate accurate health information.

Effect of Pulsing Digital Heating Devices on Skin Parameters, Subjective Pain, Mood, and Anxiety.

A common pitfall of many conventional heat therapy methods is the propensity to lose heat over time and the need for reheating and reapplication. Pain-relieving digital heating devices are now available that can be held in place on the body via adhesive or magnet and provide pulsed heat. However, the safety of such devices among different ages and skin types must be established.

Specific quinone reductase 2 inhibitors reduce metabolic burden and reverse Alzheimer's disease phenotype in mice.

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit.

Clinical Features and Biophysical Characteristics of Lips of South Asian Women.

Introduction: The vermillion lip has unique physical properties and environmental exposures make them prone to dryness and chapping. While lips contribute to facial beauty, perioral aging is highly individual and dependent on ethnicity. Specifically with regard to South Asian population, there is no other literature identified on the biophysical characteristics of the vermillion lip.

Randomized Double-Blind Placebo-Controlled Supplementation with Standardized Fruit Extracts Reduces Facial Sebum Excretion, Erythema, and Wrinkle Severity.

(TC) is a medicinal plant that exhibits antioxidant, anti-inflammatory, and antibacterial properties and that is widely used in Ayurveda and herbal formulations. However, the skin effects of TC as an oral supplement have not been studied. The objective of this study is to determine if oral TC fruit extract supplementation can modulate the skin's sebum production and reduce the appearance of wrinkles.

Anti-Extra Domain B Splice Variant of Fibronectin Antibody-Drug Conjugate Eliminates Tumors with Enhanced Efficacy When Combined with Checkpoint Blockade.

Extra domain B splice variant of fibronectin (EDB+FN) is an extracellular matrix protein (ECM) deposited by tumor-associated fibroblasts, and is associated with tumor growth, angiogenesis, and invasion. We hypothesized that EDB+FN is a safe and abundant target for therapeutic intervention with an antibody-drug conjugate (ADC). We describe the generation, pharmacology, mechanism of action, and safety profile of an ADC specific for EDB+FN (EDB-ADC).

Association of Postoperative Dieting, Exercise, Dietitian, and Surgeon Follow up With Bariatric Surgery Outcomes.

Although postoperative diet modification, exercise, and regular dietitian and surgeon follow-up are often recommended after bariatric surgery (BS), their impact on weight loss is unclear. A Retrospective chart review was conducted for patients who received sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) between August 2000 and November 2017 with telephone follow-up. Multivariable logistic regression models were used for analyses.

Malignant Pilomatricoma of the Lower Extremity: A Difficult and Rare Diagnosis.

Malignant pilomatricoma is a rare cutaneous malignancy that is commonly found on the head and neck. We present a patient with malignant pilomatricoma of the lower extremity with intralesional calcification and giant cells, confirmed by histopathology. This patient's case represents a clinically important variation of malignant pilomatricoma in an uncommon anatomical location.

Racial disparities in bariatric surgery postoperative weight loss and patient satisfaction.

Background: A growing body of evidence has demonstrated racial disparities in bariatric surgery (BS) outcomes. We aimed to investigate the impact of race on postoperative percent excess weight loss (%EWL) and patient satisfaction.

Methods: Single center retrospective study of patients who underwent BS January 2012 to November 2017.

Lichen planopilaris with significant post-inflammatory pigmentary alteration.

Lichen planopilaris is an uncommon dermatological manifestation of lichen planus of the scalp and results in cicatricial alopecia. We present a patient with lichen planopilaris and significant post-inflammatory pigmentary alteration, confirmed by histopathology. The patient's case represents a clinically important variation from an expected typical pattern of dyschromia at periphery of alopecic zones in lichen planopilaris.

Effects of smoking on bariatric surgery postoperative weight loss and patient satisfaction.

Background: While general population studies have demonstrated a relationship between cigarette smoking and weight loss, this association is not well established among the bariatric patient population. Given that bariatric patients are inherently weight-concerned, understanding the effects of smoking on postoperative weight loss is essential. We examined the association of preoperative smoking, postoperative smoking and changes in smoking status with weight loss after bariatric surgery.

Characterization of Specific -α-Acetyltransferase 50 (Naa50) Inhibitors Identified Using a DNA Encoded Library.

Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds ( and ) to understand their mechanism of action. These data were also used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate.

LC/MS Methods for Studying Lysosomal ADC Catabolism.

A critical component of antibody-drug conjugate (ADC) development is identification or verification of the active released entity upon cellular uptake and exposure to lysosomal enzymes. Coupled with LC/MS, commercial human lysosomal preparations can be used as an in vitro tool to explore the release characteristics of new ADCs, and gain information on potential metabolic or chemical liabilities of new payload structures. A general method for approaching this is described for cathepsin B-cleavable as well as non-cleavable ADCs, and opportunities for tailoring the method to specific cases are indicated.

Quick Building Blocks (QBB): An Innovative and Efficient Business Model To Speed Medicinal Chemistry Analog Synthesis.

Many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores to provide reliable access to large numbers of building blocks (BB) for the synthesis of new molecules, especially for the timely design and execution of parallel (library) synthesis. Recognizing budget and logistical limitations, we required a more economically scalable process to provide diverse BB. We disclose a novel business partnership that achieves the goals of just-in-time, economical access to commercial BB that increases chemical space coverage and accelerates the synthesis of new drug candidates.

Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor.

The c-Jun NH2-terminal kinase (JNK) signaling pathway is central to the cell response to stress, inflammatory signals, and toxins. While selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7--one of two direct MAP2Ks that activate JNK. Here, using covalent virtual screening, we identify selective MKK7 covalent inhibitors.

Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S.

Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors.

To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding.