A key aspect of our discovery platform for novel in vivo probes and drug discovery candidates is the use of informatics and curated databases of small molecules with in vivo pharmacological data (Chico et al., Nat Rev Drug Disc. 2009; Chico et al, DMD, 2009; Watterson et al., PLOS ONE 2013). The focus is on deliverables that approximate this “in vivo friendly” chemical space. The pharmaco‐ and chemo‐informatic based decision process provides a filter for compound design and initial synthetic chemistry efforts as well as termination of non‐essential synthetic efforts. Pharmacological screens on initial compounds provide project‐specific filters for recursive medicinal chemistry refinement as well as yielding insights into how structure is related to function.One target area is potentially druggable serine/threonine protein kinases in the central nervous system (CNS). The molecular starting point is often an azine in the context of diversifiable molecular scaffolds, sometimes called fragments. Risk reduction for pharmacological liabilities include blood‐brain barrier penetrance, based on the estimate that only ~ 2% of drugs have adequate CNS exposure to be effective, and key metabolic liabilities such as CYP2D6 substrate status that contribute to genetic variability in toxicity or efficacy. Therefore, the platform addresses innovation and profound risk reduction for CNS candidate discovery with emergent deliverables that are higher value candidates for IND‐enabling development and the immediate delivery of highly selective in vivo tools to complement genetic and other approaches in life science projects.A rapidly accumulating body of evidence implicates stress related kinases in pathophysiology progression, with brain p38αMAPK directly implicated as a potential neurotherapeutic target for synaptic dysfunction. Activation of p38α MAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, offers a potential for enhanced pharmacological efficacy. We developed a series of novel isoform selective p38α MAPK inhibitors that are efficacious in diverse animal models of CNS disease. In addition to revising prevailing views on targeting the active site of protein kinases, the deliverables allow the community to re‐visit the hundreds of claims about p38MAPK in pathophysiology that were based on the use of multi‐kinase inhibitors or genetic approaches that perturb the in vivo interactome and limit causal links to phenotypes. Final stage optimization driven by pharmacokinetics, safety, biodistribution, and target engagement provided candidates for drug development. A summary of one candidate in development, MW150 (Roy et al., 2015 ACS Chem Neurosci), documents the success of the platform for resolving major barriers encountered in previous drug development campaigns.Support or Funding InformationSupported by NIH awards AG031311, NS056051, AG043415, AG050636 and funds from the ADDF.