Small molecules and their impact in drug discovery: A perspective on the occasion of the 125th anniversary of the Bayer Chemical Research Laboratory.

The year 2021 marks the 125th anniversary of the Bayer Chemical Research Laboratory in Wuppertal, Germany. A significant number of prominent small-molecule drugs, from Aspirin to Xarelto, have emerged from this research site. In this review, we shed light on historic cornerstones of small-molecule drug research, discussing current and future trends in drug discovery as well as providing a personal outlook on the future of drug research with a focus on small molecules.

Cardiac output improvement by pecavaptan: a novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure.

AIMS: Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short-term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long-term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in pre-clinical HF models. METHODS AND RESULTS: In vitro IC50 determination in recombinant cell lines revealed similar receptor selectivity profiles (V2:V1a) of tolvaptan and pecavaptan for human and dog AVP receptors, respectively. Two canine models were used to compare haemodynamic and aquaretic effects: (i) anaesthetised dogs with tachypacing-induced HF, and (ii) conscious telemetric dogs with a non-invasive cardiac output (CO) monitor. Tolvaptan and pecavaptan exhibited no differences in urinary output. In HF dogs, pecavaptan counteracted the AVP-induced increase in afterload and decrease in CO (pecavaptan: 1.83 ± 0.31 L/min; vs. tolvaptan: 1.46 ± 0.07 L/min, P < 0.05). In conscious telemetric animals, pecavaptan led to a significant increase in CO (+0.26 ± 0.17 L/min, P = 0.0086 vs. placebo), in cardiac index (+0.58 ± 0.39 L/min/m2 , P = 0.009 vs. placebo) and a significant decrease in total peripheral resistance (-5348.6 ± 3601.3 dyn × s/cm5 , P < 0.0001 vs. placebo), whereas tolvaptan was without any significant effect. CONCLUSIONS: Simultaneous blockade of vascular V1a and renal V2 receptors efficiently induces aquaresis and counteracts AVP-mediated haemodynamic aggravation in HF models. Dual V1a/V2 antagonism may lead to improved outcomes in HF.

Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney disease.

Oxidative stress is a key concept in basic, translational, and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. Although attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically have gained further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells, and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular antioxidative glutathione stores. Vanin-1-deficient mice were shown to be protected against oxidative stress damage. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress-related acute or chronic kidney injury as well. By studying renal ischemia-reperfusion injury in Col4α3-/- (Alport syndrome) mice and in vitro hypoxia-reoxygenation in human proximal tubular cells we found that treatment with a selective and potent Vanin-1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigation and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.

Vascular Protection and Decongestion Without Renin-Angiotensin-Aldosterone System Stimulation Mediated by a Novel Dual-Acting Vasopressin V1a/V2 Receptor Antagonist.

Increased plasma vasopressin levels have been shown to be associated with the progression of congestive heart failure. Vasopressin mediates water retention by renal tubular V2 receptor activation as well as vasoconstriction, cardiac hypertrophy, and fibrosis through V1a receptor activation. Therefore, we developed a novel, dual-acting vasopressin receptor antagonist, BAY 1753011, with almost identical Ki-values of 0.5 nM at the human V1a receptor and 0.6 nM at the human V2 receptor as determined in radioactive binding assays. Renal V2 antagonism by BAY 1753011 was compared with the loop diuretic furosemide in acute diuresis experiments in conscious rats. Similar diuretic efficacy was found with 300-mg/kg furosemide (maximal diuretic response) and 0.1-mg/kg BAY 1753011. Furosemide dose-dependently induced plasma renin and angiotensin I levels, while an equiefficient diuretic BAY 1753011 dose did not activate the renin-angiotensin system. BAY 1753011 dose-dependently decreased the vasopressin-induced expression of the profibrotic/hypertrophic marker plasminogen activator inhibitor-1 and osteopontin in rat cardiomyocytes, while the selective V2 antagonist satavaptan was without any effect. The combined vascular V1a-mediated and renal V2-mediated properties as well as the antihypertrophic/antifibrotic activity enable BAY 1753011 to become a viable treatment option for oral chronic treatment of congestive heart failure.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

AIMS: To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODS: The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). RESULTS: In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. CONCLUSIONS: BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.

Prediction of a potentially effective dose in humans for BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling.

AIMS: The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60-5521, in humans. METHODS: A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60-5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTS: The PBPK approach predicts a greater extent of distribution for BAY 60-5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60-5521 of 51 mg in humans. CONCLUSION: The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60-5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.

Chromanol derivatives--a novel class of CETP inhibitors.

Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process.

Differentiation of arginine vasopressin antagonistic effects by selective V2 versus dual V2/V1a receptor blockade in a preclinical heart failure model.

Arginine vasopressin (AVP) is increased in patients with heart failure (HF). Its actions are linked to free water reabsorption (V2-) and arteriolar vasoconstriction (V1a receptor). AVP can exacerbate the cardiorenal syndrome with excess fluid retention and afterload increase. Tolvaptan (TOL; selective V2 antagonist) and Conivaptan (CON; dual V1a/V2 antagonist) are two AVP antagonists that counteract the action of AVP with distinct profiles. We investigated the therapeutic effects of CON and TOL in an acute HF model. Mongrel dogs were paced continuously at 220 beats/min. After 14 days, the animals underwent acute testing. Dogs were instrumented to measure cardiac output, blood pressure, pulmonary artery pressure, and left ventricular dP/dtmax. Additionally, during the acute experiments, vasopressin was infused intravenously (4 mU/kg/min) to achieve constant and controlled pathophysiological levels of AVP. Subsequently, animals received either CON or TOL (n = 6; 0.1-mg/kg bolus). There were no significant differences in effect on mean arterial pressure, dP/dtmax, central venous pressure, and urine output between CON and TOL. In contrast, cardiac output increased by 0.15 l/min after CON and decreased by 0.6 l/min after TOL (P < 0.01). Accordingly, the total peripheral resistance increased after TOL by 250 dyn*s/cm and decreased after CON by 125 dyn*s/cm (P < 0.01). In conclusion, it was demonstrated that in an acute HF model, CON lowered, whereas TOL increased afterload. The results suggest that dual V1a/V2 blockade in the acute HF setting could be beneficial compared with selective V2 blockade. Chronic experiments are needed to determine whether this finding can translate into a sustained clinical advantage.

Cholesteryl ester transfer protein and its inhibition.

Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidemia. However, discussions regarding the role of CETP-mediated lipid transfer in the development of atherosclerosis and CETP inhibition as a potential strategy for prevention of atherosclerosis have been controversial. Although many animal studies support the hypothesis that inhibition of CETP activity may be beneficial, negative phase III studies on clinical endpoints with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents. The review provides an update on current understanding of the molecular mechanisms involved in CETP activity and its inhibition.

Novel tetrahydrochinoline derived CETP inhibitors.

In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifications led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic properties for clinical development.

Novel heterocyclic thyromimetics. Part 2.

Novel heterocyclic thyromimetics are presented carrying carboxy-substituted benzofurans or sulfur containing heterocycles, as replacements for the amino acid side chain of T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. The lack of isoform selectivity demonstrated with isoform-selective transient THR transfection assays has been confirmed by corresponding in vivo studies.

In silico ADMET traffic lights as a tool for the prioritization of HTS hits.

The need for in silico characterization of HTS hit structures as part of a data-driven hit-selection process is demonstrated. A solution is described in the form of an in silico ADMET traffic light and PhysChem scoring system. This has been extensively validated with in-house data at Bayer, published data, and a collection of launched small-molecule oral drugs.

Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits.

Drug-like and lead-like hits derived from HTS campaigns provide good starting points for lead optimization. However, too strong emphasis on potency as hit-selection parameter might hamper the success of such projects. A detailed absorption, distribution, metabolism, excretion and toxicology (ADME-Tox) profiling is needed to help identify hits with a minimum number of (known) liabilities. This is particularly true for drug-like hits. Herein, we describe how to break down large numbers of screening hits and we provide a comprehensive overview of the strengths and weaknesses for each structural class. The overall profile (e.g. ligand efficiency, selectivity and ADME-Tox) is the distinctive feature that will define the priority for follow-up.

Dibenzodioxocinones--a new class of CETP inhibitors.

Derivatives of the natural product 11-hydroxy-3-[(S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5H,7H-dibenzo[b,g][1,5]dioxocin-5-one 1 were studied as novel CETP inhibitors. Compound 2 was identified from HTS as a micromolar inhibitor. The compound suffered from very low stability in plasma. Optimisation by partial synthesis started from 1 and led to low-nanomolar inhibitors with good stability in rat plasma.

Novel heterocyclic thyromimetics.

Novel heterocycle-fused thyromimetics are presented carrying indoles or indazoles instead of the phenolic group in T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. Moderate THRbeta selectivity (approx. 10-fold) was observed in the indole series using isoform-selective transient THR transfection assays.