Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).

Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1. Using a structure-based drug design approach, the kinase selectivity of the molecules was significantly improved by inducing and stabilizing an unusual P-loop folded binding mode. The metabolic liabilities of the initial 7-azaindole high-throughput screening hit were mitigated by addressing a key metabolic soft spot along with physicochemical property-based optimization. The resulting spiro-azaindoline HPK1 inhibitors demonstrated improved in vitro ADME properties and the ability to induce cytokine production in primary human T-cells.

"Evidence-debased medicine" and the integrity of the medical profession.

Patients trust physicians to prescribe based on their fiduciary duty to act in the best interests of their patients, and physicians prescribe based on confidence in research data and clinical guidelines. Recent reports erode confidence in evidence-based medicine. Through self-regulation and a willingness to change, the medical profession can assert its status as a profession distinct from outside influence, serving one interest: the healthcare of patients and the public.

Piperidine-derived gamma-secretase modulators.

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

Discovery of N-benzyl-2-[(4S)-4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl]-N-isopropylacetamide, an orally active, gut-selective CCK1 receptor agonist for the potential treatment of obesity.

We describe the design, synthesis, and structure-activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents.

Depression in primary care.

Depression is common in primary care settings, affecting at least 10% of primary care patients. It carries medical and psychiatric comorbidity, increasing the risk of cardiovascular disease, diabetes, hypertension, stroke, medically unexplained (functional) symptoms, chronic pain, anxiety disorders, and substance abuse. Diagnosis and treatment are straightforward for many patients. The greatest current challenge is to recognize and relieve symptoms of treatment-resistant depression. This article reviews current approaches to diagnosing and treating depression, especially treatment-resistant forms of depression.