CBS-3595

An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.

The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.