Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

Abstract

As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

“…EC 50 = 64 nM (FLIPR) [104] Another analysis of drug discovery compounds from different development stages concluded that marketed drugs and Phase II compounds have typically LLE>5 and LELP<10 [142]. This observation was in line with a Pfizer study concluding that compounds having LELP>10 have much higher chance for attrition during clinical development [143]. The analysis of mGluR2 PAM compounds in the LLE-LELP space (Figure 22) revealed that the vast majority of published compounds fail to meet both LLE>5 and LELP<10 criteria.…”

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

“…Since then, a number of investigators have generated more quantitatively correlated subsets of molecular physicochemical properties related to the absorption, solubility, permeability, oral bioavailability, target specificity, and toxicity of drugs and Additional information on the properties of drug-like molecules can be found in [74][75][76] clinically evaluated molecules [15][16][17][18][19][20][21][22][23]. These parameters have been used to assess the relative probability of success of clinical lead optimization research for specific drug-like compounds that have demonstrated proof of concept in subsequent clinical testing [15][16][17][18][19][20][21][22][23]. Recently, Wager et al [24] analyzed currently marketed drugs for a variety of central nervous system (CNS) disorders and developed a multi-parameter optimization (MPO) score, which is calculated from six in silico physicochemical properties (ClogP, ClogD, TPSA, MW, HBD, and pK a ).…”

“…Abad-Zapatero and Metz [25] illustrated the importance of binding efficiency (BEI) for a target as defined by (pIC 50 )/(molecular weight (MW)/ 1,000)), which is a measure of target potency relative to MW. This parameter is based on the hypothesis that increasing the potency of compounds within a chemical series solely by increasing the MW is less likely to improve the drug-like properties of the series relative to increasing the intrinsic binding efficiency [23]. For many CNS drugs (e.g., G-protein-coupled receptor antagonists), it can be assumed that a lead-like molecules would have an IC 50 …”

Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

“…25 The latter two goals were set to minimize brain exposure. 26,27 With the discovery of 1, we had optimized the indane C(5) heteroaryl group as the 6-methyl-4-pyrimidine and chose to investigate polar replacements of the 4-methoxyphenyl group of 2.…”