ABSTRACT
Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
Subject(s)
Asthma/drug therapy , Neurogenic Inflammation/drug therapy , Pain/drug therapy , Pruritus/drug therapy , Pyridines/pharmacology , Pyridines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , TRPA1 Cation Channel/antagonists & inhibitors , Adolescent , Adult , Animals , Cohort Studies , Disease Models, Animal , Dogs , Double-Blind Method , Female , Guinea Pigs , Healthy Volunteers , Humans , Isothiocyanates/administration & dosage , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Pain/chemically induced , Pruritus/chemically induced , Rats , Rats, Sprague-Dawley , TRPA1 Cation Channel/deficiency , Treatment Outcome , Young AdultABSTRACT
The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.
Subject(s)
Indazoles/chemistry , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Drug Discovery , Hydrogen BondingABSTRACT
A series of α-aryl pyrrolidine sulfonamide TRPA1 antagonists were advanced from an HTS hit to compounds that were stable in liver microsomes with retention of TRPA1 potency. Metabolite identification studies and physicochemical properties were utilized as a strategy for compound design. These compounds serve as starting points for further compound optimization.