Sulfonamido-aryl ethers as bradykinin B1 receptor antagonists.

The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.

Heterocyclic replacements for benzene: Maximising ADME benefits by considering individual ring isomers.

The impact of replacing a mono-substituted benzene (phenyl) ring with thirty three aromatic and nine aliphatic heterocycles on nine ADME-related screens (solubility, lipophilicity, permeability, protein binding CYP450 inhibition and metabolic clearance) was assessed using matched molecular pair analysis. The results indicate that the influence on the ADME profile can differ significantly depending on the ring identity and importantly on the individual regioisomers that are possible for some rings. This information enables the medicinal chemist to make an informed choice about which rings and regioisomers to employ as mono-substituted benzene replacements, based upon the knowledge of how such replacements are likely to influence ADME-related parameters, for example to target higher solubility whilst avoiding CYP450 liabilities.

Potent and orally bioavailable non-peptide antagonists at the human bradykinin B(1) receptor based on a 2-alkylamino-5-sulfamoylbenzamide core.

The bradykinin B(1) receptor is rapidly induced after inflammation or tissue trauma and appears to play an important role in the maintenance of hyperalgesia in inflammatory conditions. Here, we describe the optimization process to identify novel, potent non-peptide human B(1) receptor antagonists based on a 2-alkylamino-5-sulfamoylbenzamide core. Optimized derivatives are selective, functional B(1) antagonists with low nanomolar affinity and exhibit oral bioavailability in animals.

Nonpeptide bradykinin B2 receptor antagonists: conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists.

The 1-(2-nitrophenyl)thiosemicarbazide (TSC) derivative, (S)-1-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl]pyrrolidine-2-carboxylic acid [2-[(2-dimethylaminoethyl)methylamino]ethyl]amide (bradyzide; (S)-4), was recently disclosed as a novel, potent, orally active nonpeptide bradykinin (BK) B2 receptor antagonist. The compound inhibited the specific binding of [3H]BK to NG108-15 cell membrane preparations (rodent neuroblastoma-glioma) expressing B2 receptors with a K(i) of 0.5 +/- 0.2 nM. Compound (S)-4 also demonstrated oral efficacy against Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in rats with an ED50 value of 0.84 micromol/kg. After we optimized the terminal binding determinants projecting from the TSC framework, we found that it was possible to replace the potentially toxicophoric nitro and divalent sulfur moieties with only a 15-fold loss in binding affinity ((S)-14a). However, bradyzide and its congeners were found to have much lower affinities for cloned human B2 receptors, expressed in Cos-7 cells. The hitherto synthesized TSC series was screened against the human B2 receptor, and the dibenzosuberane (DBS) pharmacophore emerged as the key structural requirement for potency. Incorporation of this group resulted in a series of derivatives ((S)-14d,e and 19b-d) with K(i) ranges of 10.7-176 nM in NG108-15 cells (expressing the rodent B2 receptor) and 0.79-253 nM in Cos-7 cells (expressing the human B2 receptor). There was no evidence of agonist activity with any of the nonpeptides in any of the cell lines tested. In vivo, oral administration of compound 19c reversed FCA-induced and turpentine-induced mechanical hyperalgesia in rodents with ED50 values of 0.027 and 0.32 micromol/kg, respectively. The selectivity profiles of compounds (S)-14f and (S)-14g were also assessed to determine the conformational and/or steric preferences of the double-ring arrangement. The affinity of (S)-14 g for the human B2 receptor suggested that it may be a hydrophobic interaction with the ethane bridge of the DBS moiety that accounts for the increased potency of compounds (S)-14d,e and 19b,c at this receptor, by favoring a binding mode inaccessible to the unsubstituted diphenylmethyl derivative, (S)-4.

Physicochemical descriptors of aromatic character and their use in drug discovery.

Published physicochemical descriptors of molecules that convey aromaticity-related character are reviewed in the context of drug design and discovery. Studies that have employed aromatic descriptors are discussed, and several descriptors are compared and contrasted.

How drug-like are 'ugly' drugs: do drug-likeness metrics predict ADME behaviour in humans?

Using a published drug-likeness score based on the calculated physicochemical properties of marketed oral drugs (quantitative estimate of drug-likeness, QED) and published human data, high-scoring and low-scoring drugs were compared to determine how well the score correlated with their actual pharmaceutical and pharmacokinetic (PK) profiles in humans. Drugs with high QED scores exhibit higher absorption and bioavailability, are administered at lower doses and have fewer drug-drug interaction warnings, P-glycoprotein interactions and absorption issues due to a food effect. By contrast, the high-scoring drugs exhibit similar behaviour to low-scoring drugs with respect to free fraction in plasma, extent of gut-wall metabolism, first-pass hepatic extraction, elimination half-life, clearance, volume of distribution and frequency of dosing.

Should medicinal chemists do molecular modelling?

In this article we discuss the pros and cons of medicinal chemists undertaking three-dimensional (3D) computer-aided drug design (CADD) activities for themselves, from the viewpoint of both medicinal chemists and computational chemists. We describe how best this can be implemented, the potential benefits that can be obtained and the pitfalls that are often encountered.

The graphical representation of ADME-related molecule properties for medicinal chemists.

The importance of striving for and maintaining drug-like physicochemical properties during the hit and lead optimization process is now well documented, and many published studies have suggested optimal ranges and/or limits for key molecule descriptors such as size, lipophilicity, H-bonding characteristics, rotatable bond and aromatic ring counts, particularly with regard to the design of orally administered drugs. The aim of this article is to review various approaches that have been used to represent molecule properties graphically in the context of oral 'drug likeness', with the goal of improving the decision making of medicinal chemists during the drug discovery process.

The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types.

The impact of carboaromatic, heteroaromatic, carboaliphatic and heteroaliphatic ring counts and fused aromatic ring count on several developability measures (solubility, lipophilicity, protein binding, P450 inhibition and hERG binding) is the topic for this review article. Recent results indicate that increasing ring counts have detrimental effects on developability in the order carboaromatics≫heteroaromatics>carboaliphatics>heteroaliphatics, with heteroaliphatics exerting a beneficial effect in many cases. Increasing aromatic ring count exerts effects on several developability parameters that are lipophilicity- and size-independent, and fused aromatic systems have a beneficial effect relative to their nonfused counterparts. Increasing aromatic ring count has a detrimental effect on human bioavailability parameters, and heteroaromatic ring count (but not other ring counts) has increased over time in marketed oral drugs.

The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design?

The impact of aromatic ring count (the number of aromatic and heteroaromatic rings) in molecules has been analyzed against various developability parameters - aqueous solubility, lipophilicity, serum albumin binding, CyP450 inhibition and hERG inhibition. On the basis of this analysis, it was concluded that the fewer aromatic rings contained in an oral drug candidate, the more developable that candidate is probably to be; in addition, more than three aromatic rings in a molecule correlates with poorer compound developability and, thus, an increased risk of attrition in development. Data are also presented that demonstrate that even within a defined lipophilicity range, increased aromatic ring count leads to decreased aqueous solubility.

Analysis of the calculated physicochemical properties of respiratory drugs: can we design for inhaled drugs yet?

From an analysis of calculated physicochemical properties for 81 currently marketed respiratory drugs, compounds administered via the inhaled/intranasal routes have a higher polar surface area, a higher molecular weight, and a trend toward lower lipophilicity, when compared with their orally administered counterparts. Ranges of physicochemical space are described for the 29 drugs administered by the inhaled or intranasal routes.