Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery

Abstract

Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochemical properties. The CNS MPO tool has helped to increase the percentage of compounds nominated for clinical development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the number of compounds submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development.

Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer’s disease

“…After the discovery by Weggen et al [31] that a subset of NSAIDs could selectively lower Aβ 42 without affecting the initial cleavage step by GS (ε cleavage), a lot of research was dedicated to finding new generations of compounds that could mediate similar effects [20, 32]. In our quest to discover GSMs that satisfy all known empirical rules of good central nervous system (CNS) drug-like properties [41–43], we synthesized FRM-36143 (Bursavich MG, Harrison BA, Costa DE, Hodgdon HE, Freeman EA, Hrdlicka LA, Kapadnis S, Moffit J, Murphy DA, Patzke H, Tang C, Wen M, Burnett DA, Koenig G, Blain JF. Design, synthesis and evaluation of a novel series of oxadiazine Gamma Secretase Modulators for familial Alzheimer’s disease, Submitted).…”

Leveraging chromatography based physicochemical properties for efficient drug design

“…The CNS MPO desirability method is quite simple, with parameters derived from medicinal chemistry best practices, and it is able to balance multiple variables while avoiding hard cut-offs. It demonstrated a good correlation between a high score (> 4 out of a possible max of 6) and good in vitro ADME properties [12,78]. …”

Assessing molecular scaffolds for CNS drug discovery

“…Scientists at Pfizer have recently shown that use of their CNS Multi-Parameter Optimisation (MPO) scoring tool has increased the percentage of clinical candidates discovered that possess desirable ADMET properties and cross the BBB [15]. This tool assigns a desirability score (0.05-1) for six physicochemical properties: MW; lipophilicity, calculated partition coefficient (cLogP); distribution coefficient at pH = 7.4 (cLogD); most basic centre (pKa); number of hydrogen bond donors (HBD) and topological polar surface area (TPSA) [16].…”

“…In their original study, the authors showed that a set of 119 marketed CNS drugs had generally higher CNS MPO scores than a set of 108 Pfizer CNS candidates [16]. Moreover, after routine application of the tool, nominated CNS candidates had been shifted towards more polar and less lipophilic property space [15]. Simplicity of application and a clear mechanistic link allow chemists to understand how modification of molecular structure changes the CNS MPO score.…”