22 research outputs found
Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery
Gαq-containing G proteins regulate B cell selection and survival and are required to prevent B cell–dependent autoimmunity
Survival of mature B cells is regulated by B cell receptor and BAFFR-dependent signals. We show that B cells from mice lacking the Gαq subunit of trimeric G proteins (Gnaq−/− mice) have an intrinsic survival advantage over normal B cells, even in the absence of BAFF. Gnaq−/− B cells develop normally in the bone marrow but inappropriately survive peripheral tolerance checkpoints, leading to the accumulation of transitional, marginal zone, and follicular B cells, many of which are autoreactive. Gnaq−/− chimeric mice rapidly develop arthritis as well as other manifestations of systemic autoimmune disease. Importantly, we demonstrate that the development of the autoreactive B cell compartment is the result of an intrinsic defect in Gnaq−/− B cells, resulting in the aberrant activation of the prosurvival factor Akt. Together, these data show for the first time that signaling through trimeric G proteins is critically important for maintaining control of peripheral B cell tolerance induction and repressing autoimmunity
Technically Extended MultiParameter Optimization (TEMPO): An Advanced Robust Scoring Scheme To Calculate Central Nervous System Druggability and Monitor Lead Optimization
At the discovery stage, it is important
to understand the drug
design concepts for a CNS drug compared to those for a non-CNS drug.
Previously, we published on ideal CNS drug property space and defined
in detail the physicochemical property distribution of CNS versus
non-CNS oral drugs, the application of radar charting (a graphical
representation of multiple physicochemical properties used during
CNS lead optimization), and a recursive partition classification tree
to differentiate between CNS- and non-CNS drugs. The objective of
the present study was to further understand the differentiation of
physicochemical properties between CNS and non-CNS oral drugs by the
development and application of a new CNS scoring scheme: Technically
Extended MultiParameter Optimization (TEMPO). In this multiparameter
method, we identified eight key physicochemical properties critical
for accurately assessing CNS druggability: (1) number of basic amines,
(2) carbon–heteroatom (non-carbon, non-hydrogen) ratio, (3)
number of aromatic rings, (4) number of chains, (5) number of rotatable
bonds, (6) number of H-acceptors, (7) computed octanol/water partition
coefficient (AlogP), and (8) number of nonconjugated C atoms in nonaromatic
rings. Significant features of the CNS-TEMPO penalty score are the
extension of the multiparameter approach to generate an accurate weight
factor for each physicochemical property, the use of limits on both
sides of the computed property space range during the penalty calculation,
and the classification of CNS and non-CNS drug scores. CNS-TEMPO significantly
outperformed CNS-MPO and the Schrödinger QikProp CNS parameter
(QP_CNS) in evaluating CNS drugs and has been extensively applied
in support of CNS lead optimization programs
The Effect of Pyrrolo[3,4-C]Carbazole Derivatives on Spinal Cord Chat Activity
Pyrrolo[3,4-c]carbazole derivatives were prepared as potential neurotrophic agents. The compounds were assayed for their ability to stimulate choline acetyltransferase (ChAT) activity in embryonic rat spinal cord cultures. These simplified K252a derivatives, although less potent and efficacious, have led to the identification of minimal structural requirements for K252a neurotrophic activity
Development and Scale-Up of an Optimized Route to the Pyridazin-3-one Histamine H3 Receptor Antagonist CEP-32215
The
evolution of the process to prepare CEP-32215, 3-(1′-cyclobutylspiro[4H-1,3-benzodioxine-2,4′-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazine-6-one,
is presented. Two routes detailing preparation of supplies for biological
screening are discussed along with the optimized fit-for-purpose process
used to prepare several hundred grams for preclinical testing. Details
on the development of the formation of the key spiroketal moiety are
presented along with the discovery of a novel Suzuki coupling approach
for synthesis of the backbone of the molecule
Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery
The central nervous system (CNS) is the major area that
is affected
by aging. Alzheimer’s disease (AD), Parkinson’s disease
(PD), brain cancer, and stroke are the CNS diseases that will cost
trillions of dollars for their treatment. Achievement of appropriate
blood–brain barrier (BBB) penetration is often considered a
significant hurdle in the CNS drug discovery process. On the other
hand, BBB penetration may be a liability for many of the non-CNS drug
targets, and a clear understanding of the physicochemical and structural
differences between CNS and non-CNS drugs may assist both research
areas. Because of the numerous and challenging issues in CNS drug
discovery and the low success rates, pharmaceutical companies are
beginning to deprioritize their drug discovery efforts in the CNS
arena. Prompted by these challenges and to aid in the design of high-quality,
efficacious CNS compounds, we analyzed the physicochemical property
and the chemical structural profiles of 317 CNS and 626 non-CNS oral
drugs. The conclusions derived provide an ideal property profile for
lead selection and the property modification strategy during the lead
optimization process. A list of substructural units that may be useful
for CNS drug design was also provided here. A classification tree
was also developed to differentiate between CNS drugs and non-CNS
oral drugs. The combined analysis provided the following guidelines
for designing high-quality CNS drugs: (i) topological molecular polar
surface area of <76 Å<sup>2</sup> (25–60 Å<sup>2</sup>), (ii) at least one (one or two, including one aliphatic
amine) nitrogen, (iii) fewer than seven (two to four) linear chains
outside of rings, (iv) fewer than three (zero or one) polar hydrogen
atoms, (v) volume of 740–970 Å<sup>3</sup>, (vi) solvent
accessible surface area of 460–580 Å<sup>2</sup>, and
(vii) positive QikProp parameter CNS. The ranges within parentheses
may be used during lead optimization. One violation to this proposed
profile may be acceptable. The chemoinformatics approaches for graphically
analyzing multiple properties efficiently are presented
Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery
The central nervous system (CNS) is the major area that
is affected
by aging. Alzheimer’s disease (AD), Parkinson’s disease
(PD), brain cancer, and stroke are the CNS diseases that will cost
trillions of dollars for their treatment. Achievement of appropriate
blood–brain barrier (BBB) penetration is often considered a
significant hurdle in the CNS drug discovery process. On the other
hand, BBB penetration may be a liability for many of the non-CNS drug
targets, and a clear understanding of the physicochemical and structural
differences between CNS and non-CNS drugs may assist both research
areas. Because of the numerous and challenging issues in CNS drug
discovery and the low success rates, pharmaceutical companies are
beginning to deprioritize their drug discovery efforts in the CNS
arena. Prompted by these challenges and to aid in the design of high-quality,
efficacious CNS compounds, we analyzed the physicochemical property
and the chemical structural profiles of 317 CNS and 626 non-CNS oral
drugs. The conclusions derived provide an ideal property profile for
lead selection and the property modification strategy during the lead
optimization process. A list of substructural units that may be useful
for CNS drug design was also provided here. A classification tree
was also developed to differentiate between CNS drugs and non-CNS
oral drugs. The combined analysis provided the following guidelines
for designing high-quality CNS drugs: (i) topological molecular polar
surface area of <76 Å<sup>2</sup> (25–60 Å<sup>2</sup>), (ii) at least one (one or two, including one aliphatic
amine) nitrogen, (iii) fewer than seven (two to four) linear chains
outside of rings, (iv) fewer than three (zero or one) polar hydrogen
atoms, (v) volume of 740–970 Å<sup>3</sup>, (vi) solvent
accessible surface area of 460–580 Å<sup>2</sup>, and
(vii) positive QikProp parameter CNS. The ranges within parentheses
may be used during lead optimization. One violation to this proposed
profile may be acceptable. The chemoinformatics approaches for graphically
analyzing multiple properties efficiently are presented
Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery
The central nervous system (CNS) is the major area that
is affected
by aging. Alzheimer’s disease (AD), Parkinson’s disease
(PD), brain cancer, and stroke are the CNS diseases that will cost
trillions of dollars for their treatment. Achievement of appropriate
blood–brain barrier (BBB) penetration is often considered a
significant hurdle in the CNS drug discovery process. On the other
hand, BBB penetration may be a liability for many of the non-CNS drug
targets, and a clear understanding of the physicochemical and structural
differences between CNS and non-CNS drugs may assist both research
areas. Because of the numerous and challenging issues in CNS drug
discovery and the low success rates, pharmaceutical companies are
beginning to deprioritize their drug discovery efforts in the CNS
arena. Prompted by these challenges and to aid in the design of high-quality,
efficacious CNS compounds, we analyzed the physicochemical property
and the chemical structural profiles of 317 CNS and 626 non-CNS oral
drugs. The conclusions derived provide an ideal property profile for
lead selection and the property modification strategy during the lead
optimization process. A list of substructural units that may be useful
for CNS drug design was also provided here. A classification tree
was also developed to differentiate between CNS drugs and non-CNS
oral drugs. The combined analysis provided the following guidelines
for designing high-quality CNS drugs: (i) topological molecular polar
surface area of <76 Å<sup>2</sup> (25–60 Å<sup>2</sup>), (ii) at least one (one or two, including one aliphatic
amine) nitrogen, (iii) fewer than seven (two to four) linear chains
outside of rings, (iv) fewer than three (zero or one) polar hydrogen
atoms, (v) volume of 740–970 Å<sup>3</sup>, (vi) solvent
accessible surface area of 460–580 Å<sup>2</sup>, and
(vii) positive QikProp parameter CNS. The ranges within parentheses
may be used during lead optimization. One violation to this proposed
profile may be acceptable. The chemoinformatics approaches for graphically
analyzing multiple properties efficiently are presented