Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective

Abstract

New strategies to potentially improve drug safety and efficacy emerge with allosteric programs. Biased allosteric modulators can be designed with high subtype selectivity and defined receptor signaling endpoints, however, selecting the most meaningful parameters for optimization can be perplexing. Historically, "potency hunting" at the expense of physicochemical and pharmacokinetic optimization has led to numerous tool compounds with excellent pharmacological properties but no path to drug development. Conversely, extensive physicochemical and pharmacokinetic screening with only post hoc bias and allosteric characterization has led to inefficacious compounds or compounds with on-target toxicities. This field is rapidly evolving with new mechanistic understanding, changes in terminology, and novel opportunities. The intent of this digest is to summarize current understanding and debates within the field. We aim to discuss, from a medicinal chemistry perspective, the parameter choices available to drive SAR.

Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment

“…Further increase of potency could be achieved by new analogue synthesis based on structural biology information as demonstrated in our work. In addition, it is also known that discrepancies between in vitro and in cellulo potencies can be associated with targets, such as RAS, with high conformational variability and allosteric modulators 49 , 50 . Furthermore, the discrepancy could be exacerbated by permeability, efflux and free drug vs total drug availability, target location and biochemical state.…”

“Selective” Class C G Protein-Coupled Receptor Modulators Are Neutral or Biased mGlu5Allosteric Ligands

“…A further contributor to misinterpretation of SAR is the reliance on functional assays with orthosteric ligands to measure changes in modulator potency. Functional modulator IC 50 /EC 50 values alone are unreliable, as potency represents a composite of allosteric cooperativity, affinity and intrinsic efficacy factors (Gregory et al, 2010;Lindsley et al, 2016;Johnstone and Albert, 2017). Each factor has its own SAR to consider during compound optimization and modification.…”

“…SAR efforts aiming to eliminate off-target affinity may be misinterpreted if the ligands maintain their off-target affinity but lose cooperativity. To progress subtype selective allosteric ligands there is a need to monitor each allosteric component individually (Johnstone and Albert, 2017). Modulator affinity estimates derived from functional data using operational models of allosterism are well correlated with binding affinity estimates, at least for mGlu 5 (Gregory et al, 2012).…”

Effects and sites of action of a M1 receptor positive allosteric modulator on colonic motility in rats and dogs compared with 5‐HT4 agonism and cholinesterase inhibition

“…In the case of T440, when it was administered orally once daily for 5 days, the fecal pellet output was almost identical on day 1 and day 5, suggesting no tolerance occurred. Generally, long‐lasting activation of GPCR causes desensitization of the receptor by internalization 8 . In the case of the M1PAM, at least in the rat study, lack of tolerance suggests it could be utilized in the clinical setting as a daily medication for chronic constipation.…”

“…Drug therapies include anticholinesterases, such as neostigmine, 2 5‐HT 4 receptor agonists, such as prucalopride, 3,4 and recently, muscarinic receptor 1 positive allosteric modulators (M1PAMs) have been suggested to provide a possible treatment 5‐7 . PAMs have provoked much interest as therapeutic agents because, in comparison to direct agonists that stimulate receptors independent of their physiological state of engagement, PAMs have effects in proportion to physiological levels of receptor activation 8 . Thus, PAMs are anticipated to be more effective in augmenting physiological patterns of activity than are direct agonists.…”