The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.
The
leucine-rich repeat kinase 2 (LRRK2) protein has been genetically
and functionally linked to Parkinson’s disease (PD), a disabling
and progressive neurodegenerative disorder whose current therapies
are limited in scope and efficacy. In this report, we describe a rigorous
hit-to-lead optimization campaign supported by structural enablement,
which culminated in the discovery of brain-penetrant, candidate-quality
molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome
and offer good oral bioavailability and low projected human doses.
Furthermore, they showcase the implementation of stereochemical design
elements that serve to enable a potency- and selectivity-enhancing
increase in polarity and hydrogen bond donor (HBD) count while maintaining
a central nervous system-friendly profile typified by low levels of
transporter-mediated efflux and encouraging brain penetration in preclinical
models.
Using the HIV-1 protease binding mode of and as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral activity relative to .
The application of bicyclo[1.1.1]pentanes (BCPs) as phenyl bioisosteres has garnered significant attention, as these structural motifs can improve the physiochemical profiles of drug candidates. Despite the potential of using 1-bicyclo[1.1.1]pentylpyrazoles (BCPPs) as 1-phenylpyrazole bioisosteres, this area remains underexplored because of the relative lack of reliable synthetic methods for the preparation of BCPPs. Herein we address this synthetic gap and report the development of novel and scalable routes to generate a host of BCPPs.
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