13 research outputs found
4-Oxospiro[benzopyran-2,4'-piperidines] as class III antiarrhythmic agents. Pharmacological studies on 3,4-dihydro-1'-[2-(benzofurazan-5-yl)ethyl]-6-methanesulfonamidospiro[(2H)-1-benzopyran-2,4'-piperidin]-4-one (L-691,121)
Structure-Based Design Technology Contour and Its Application to the Design of Renin Inhibitors
It is well-known that the structure-based design approach
has had
a measurable impact on the drug discovery process in identifying novel
and efficacious therapeutic agents for a variety of disease targets.
The de novo design approach has inherent potential to generate novel
molecules that best fit into a protein binding site when compared
to all of the computational methods applied to structure-based design.
In its initial attempts, this approach did not achieve much success
due to technical hurdles. More recently, the algorithmic advancements
in the methodologies and clever strategies developed to design drug-like
molecules have improved the success rate. We describe a state-of-the-art
structure-based design technology called Contour and provide details
of the algorithmic enhancements we have implemented. Contour was designed
to create novel drug-like molecules by assembling synthetically viable
fragments in the protein binding site using a high-resolution crystal
structure of the protein. The technology consists of a sophisticated
growth algorithm and a novel scoring function based on a directional
model. The growth algorithm generates molecules by dynamically selecting
only those fragments from the fragment library that are complementary
to the binding site, and assembling them by sampling the conformational
space for each attached fragment. The scoring function embodying the
essential elements of the binding interactions aids in the rank ordering
of grown molecules and helps identify those that have high probability
of exhibiting activity against the protein target of interest. The
application of Contour to identify inhibitors against human renin
enzyme eventually leading to the clinical candidate VTP-27,999 will
be discussed here
Structure-Based Design Technology Contour and Its Application to the Design of Renin Inhibitors
It is well-known that the structure-based design approach
has had
a measurable impact on the drug discovery process in identifying novel
and efficacious therapeutic agents for a variety of disease targets.
The de novo design approach has inherent potential to generate novel
molecules that best fit into a protein binding site when compared
to all of the computational methods applied to structure-based design.
In its initial attempts, this approach did not achieve much success
due to technical hurdles. More recently, the algorithmic advancements
in the methodologies and clever strategies developed to design drug-like
molecules have improved the success rate. We describe a state-of-the-art
structure-based design technology called Contour and provide details
of the algorithmic enhancements we have implemented. Contour was designed
to create novel drug-like molecules by assembling synthetically viable
fragments in the protein binding site using a high-resolution crystal
structure of the protein. The technology consists of a sophisticated
growth algorithm and a novel scoring function based on a directional
model. The growth algorithm generates molecules by dynamically selecting
only those fragments from the fragment library that are complementary
to the binding site, and assembling them by sampling the conformational
space for each attached fragment. The scoring function embodying the
essential elements of the binding interactions aids in the rank ordering
of grown molecules and helps identify those that have high probability
of exhibiting activity against the protein target of interest. The
application of Contour to identify inhibitors against human renin
enzyme eventually leading to the clinical candidate VTP-27,999 will
be discussed here
Class III Antiarrhythmic Activity in Vivo by Selective Blockade of the Slowly Activating Cardiac Delayed Rectifier Potassium Current I
Structure-Based Design Technology Contour and Its Application to the Design of Renin Inhibitors
Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ
The development of large-scale syntheses of two beta-site
amyloid
precursor protein cleaving enzyme (BACE) inhibitors is described.
New methodologies were discovered to overcome safety and scalability
problems with existing procedures. The sterically hindered quaternary,
neopentyl stereocenter was formed in high diastereoselectivity by
the addition of a carbamoyl anion to an N-sulfinyl
ketimine. An aryl nitrile was installed by a palladium- and cyanide-free
electrophilic cyanation affected by transnitrilation of an arylmagnesium
derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine
side chain was devised based on diethyl malonate and dibenzylamine
starting materials. A mild enamine fluorination was developed for
the synthesis of a fluoroisobutylamine side chain
Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ
The development of large-scale syntheses of two beta-site
amyloid
precursor protein cleaving enzyme (BACE) inhibitors is described.
New methodologies were discovered to overcome safety and scalability
problems with existing procedures. The sterically hindered quaternary,
neopentyl stereocenter was formed in high diastereoselectivity by
the addition of a carbamoyl anion to an N-sulfinyl
ketimine. An aryl nitrile was installed by a palladium- and cyanide-free
electrophilic cyanation affected by transnitrilation of an arylmagnesium
derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine
side chain was devised based on diethyl malonate and dibenzylamine
starting materials. A mild enamine fluorination was developed for
the synthesis of a fluoroisobutylamine side chain
Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ
The development of large-scale syntheses of two beta-site
amyloid
precursor protein cleaving enzyme (BACE) inhibitors is described.
New methodologies were discovered to overcome safety and scalability
problems with existing procedures. The sterically hindered quaternary,
neopentyl stereocenter was formed in high diastereoselectivity by
the addition of a carbamoyl anion to an N-sulfinyl
ketimine. An aryl nitrile was installed by a palladium- and cyanide-free
electrophilic cyanation affected by transnitrilation of an arylmagnesium
derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine
side chain was devised based on diethyl malonate and dibenzylamine
starting materials. A mild enamine fluorination was developed for
the synthesis of a fluoroisobutylamine side chain