10 research outputs found
Challenges and Rewards in Medicinal Chemistry Targeting Cardiovascular and Metabolic Diseases
Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental
high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and
advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11?-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase
(HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes
Biomimetic Cycloaddition Approach to Tropolone Natural Products via a Tropolone Ortho-quinone Methide
Structure-Based Design and Synthesis of Potent Cyclic Peptides Inhibiting the YAP–TEAD Protein–Protein Interaction
The
YAP–TEAD protein–protein interaction (PPI) mediates
the oncogenic function of YAP, and inhibitors of this PPI have potential
usage in treatment of YAP-involved cancers. Here we report the design
and synthesis of potent cyclic peptide inhibitors of the YAP–TEAD
interaction. A truncation study of YAP interface 3 peptide identified
YAP<sup>84–100</sup> as a weak peptide inhibitor (IC<sub>50</sub> = 37 μM), and an alanine scan revealed a beneficial mutation,
D94A. Subsequent replacement of a native cation−π interaction
with an optimized disulfide bridge for conformational constraint and
synergistic effect between macrocyclization and modification at positions
91 and 93 greatly boosted inhibitory activity. Peptide <b>17</b> was identified with an IC<sub>50</sub> of 25 nM, and the binding
affinity (<i>K</i><sub>d</sub> = 15 nM) of this 17mer peptide
to TEAD1 proved to be stronger than YAP<sup>50–171</sup> (<i>K</i><sub>d</sub> = 40 nM)
Benzodioxoles: Novel Cannabinoid-1 Receptor Inverse Agonists for the Treatment of Obesity
Discovery of 4‑Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys
Inappropriately high levels of aldosterone
are associated with
many serious medical conditions, including renal and cardiac failure.
A focused screen hit has been optimized into a potent and selective
aldosterone synthase (CYP11B2) inhibitor with in vitro activity against
rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity
factor of 160 against cytochrome CYP11B1 in the last species. The
novel tetrahydroisoquinoline compound (+)-(<i>R</i>)-<b>6</b> selectively reduced aldosterone plasma levels in vivo in
a dose-dependent manner in db/db mice and cynomolgus monkeys. The
selectivity against CYP11B1 as predicted by cellular inhibition data
and free plasma fraction translated well to Synacthen challenged cynomolgus
monkeys up to a dose of 0.1 mg kg<sup>–1</sup>. This compound,
displaying good in vivo potency and selectivity in mice and monkeys,
is ideally suited to perform mechanistic studies in relevant rodent
models and to provide the information necessary for translation to
non-human primates and ultimately to man
β‑Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease
An
extensive fluorine scan of 1,3-oxazines revealed the power of
fluorine(s) to lower the p<i>K</i><sub>a</sub> and thereby
dramatically change the pharmacological profile of this class of BACE1
inhibitors. The CF<sub>3</sub> substituted oxazine <b>89</b>, a potent and highly brain penetrant BACE1 inhibitor, was able to
reduce significantly CSF Aβ40 and 42 in rats at oral doses as
low as 1 mg/kg. The effect was long lasting, showing a significant
reduction of Aβ40 and 42 even after 24 h. In contrast to <b>89</b>, compound <b>1b</b> lacking the CF<sub>3</sub> group
was virtually inactive in vivo
Design and Synthesis of Orally Bioavailable 4‑Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors
Targeting
the capsid protein of hepatitis B virus (HBV) and thus
interrupting normal capsid formation have been an attractive approach
to block the replication of HBV viruses. We carried out multidimensional
structural optimizations based on the heteroaryldihydropyrimidine
(HAP) analogue Bay41-4109 (<b>1</b>) and identified a novel
series of HBV capsid inhibitors that demonstrated promising cellular
selectivity indexes, metabolic stabilities, and in vitro safety profiles.
Herein we disclose the design, synthesis, structure–activity
relationship (SAR), cocrystal structure in complex with HBV capsid
proteins and in vivo pharmacological study of the 4-methyl HAP analogues.
In particular, the (2<i>S</i>,4<i>S</i>)-4,4-difluoroproline
substituted analogue <b>34a</b> demonstrated high oral bioavailability
and liver exposure and achieved over 2 log viral load reduction in
a hydrodynamic injected (HDI) HBV mouse model
Design and Synthesis of Orally Bioavailable 4‑Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors
Targeting
the capsid protein of hepatitis B virus (HBV) and thus
interrupting normal capsid formation have been an attractive approach
to block the replication of HBV viruses. We carried out multidimensional
structural optimizations based on the heteroaryldihydropyrimidine
(HAP) analogue Bay41-4109 (<b>1</b>) and identified a novel
series of HBV capsid inhibitors that demonstrated promising cellular
selectivity indexes, metabolic stabilities, and in vitro safety profiles.
Herein we disclose the design, synthesis, structure–activity
relationship (SAR), cocrystal structure in complex with HBV capsid
proteins and in vivo pharmacological study of the 4-methyl HAP analogues.
In particular, the (2<i>S</i>,4<i>S</i>)-4,4-difluoroproline
substituted analogue <b>34a</b> demonstrated high oral bioavailability
and liver exposure and achieved over 2 log viral load reduction in
a hydrodynamic injected (HDI) HBV mouse model
Discovery and Pre-Clinical Characterization of Third-Generation 4‑H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors
Described
herein are the discovery and structure–activity relationship
(SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines
(4-H HAPs) featuring the introduction of a C6 carboxyl group as novel
HBV capsid inhibitors. This new series of 4-H HAPs showed improved
anti-HBV activity and better drug-like properties compared to the
first- and second-generation 4-H HAPs. X-ray crystallographic study
of analogue <b>12</b> (HAP_R01) with Cp149 Y132A mutant hexamer
clearly elucidated the role of C6 carboxyl group played for the increased
binding affinity, which formed strong hydrogen bonding interactions
with capsid protein and coordinated waters. The representative analogue <b>10</b> (HAP_R10) was extensively characterized in vitro (ADMET)
and in vivo (mouse PK and PD) and subsequently selected for further
development as oral anti-HBV infection agent