Vertex Pharmaceuticals, Inc.

University of California

Aurora Biosciences Corporation

Invitrogen Corporation

Life Technologies Corporation

Vertex Pharmaceuticals (san Diego) LLC

Gregor Zlokarnik

Roger Y Tsien

Fredrick Van Goor

Martyn Botfield

Lewis R Makings

Adam R Looker

Martin Trudeau

John A DeMattei

Stefanie Roeper

Bobbianna Neubert-Langille

Michael P Ryan

Brian R Krueger

Peter D J Grootenhuis

Tom Knapp

Tim Rink

Dahrika Milfred Yap Guerette

Fredrick F Van Goor

Martyn C Botfield

Peter Diederik Jan Grootenhuis

Paul Negulescu

Peter D Grootenhuis

Dahrika Milfred Yap

John Demattei

Sara Sabina Hadida Ruah

Xiaoqing Yang

Francois Maltais

Robert B Perni

Youssef L Bennani

Gerald J Tanoury

Minzhang Chen

Patricia Nell Hurter

Young Chun Jung

William Rowe

Kirk Raymond Dinehart

Marinus Jacobus Verwijs

Raymond E Forslund

Alfredo Grossi

Kirk Overhoff

Paul A Negulescu

Christopher R Young

Luxin Feng

Dahrika Milfred Lao Yap

Peter Dj Grootenhuis

Frederick F Van Goor

Sara S Hadida Ruah

Peter DJ Grootenhuis

Frederick F Van Groor

Stefanie Roper

Bobbiana Neubert-Langille

The invention provides a process for the preparation of a compound of Formula 1, comprising coupling a carboxylic acid of Formula 2 with an aniline of Formula 3 in the presence of a coupling agent.

Process for making modulators of cystic fibrosis transmembrane conductance regulator

This invention relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is COOH or CHOH.

Modulators of cystic fibrosis transmembrane conductance regulator

This invention relates to processes and intermediates for the preparation of salts of deuterated, enantiomericallv enriched alpha-amino beta-hydroxy acids of Formula 1 wherein the variables R,R'and R&#x2032;are defined herein, and wherein the process may comprise the steps of forming a salt of a compound of Formula 1, and crystallizing said salt to give a compound of greater than 55% enantiomeric excess.

Deuterated hepatitis C protease inhibitors

The invention provides a compound, useful as an optical probe or sensor of the activity of at least one cytochrome P450 enzyme, and methods of using the compound to screen candidate drugs, and candidate drugs identified by these methods. The optical probe of the invention is a compound having the generic structure Y-L-Q, wherein Q is a chemical moiety that gives rise to optical properties in its hydroxy or hyrdoxylate, phenol or phenoxide form that are different from the optical properties that arise from its ether form.

Optical molecular sensors for cytochrome P450 activity

Substrates for &#x3b2;-lactamase of the general formula I in which one of X and Y is a fluorescent donor moiety and the other is a quencher (which may or may not re-emit); R' is selected from the group consisting of H, lower (i.e., alkyl of 1 to about 5 carbon atoms) and (CH)OH, in which n is 0 or an integer from 1 to 5; R&#x2033; is selected from the group consisting of H, physiologically acceptable metal and ammonium cations, &#x2014;CHROCO(CH)CH, &#x2014;CHROCOC (CH), acylthiomethyl, acyloxy-alpha-benzyl, delta-butyrolactonyl, methoxycarbonyloxymethyl, phenyl, methylsulphinylmethyl, beta-morpholinoethyl, dialkylaminoethyl, acyloxyalkyl, dialkylaminocarbonyloxymethyl and aliphatic, in which Ris selected from the group consisting of H and lower alkyl; A is selected from the group consisting of S, O, SO, SOand CH; and Z&#x2032; and Z&#x2033; are linkers for the fluorescent donor and quencher moieties. Methods of assaying &#x3b2;-lactamase activity and monitoring expression in systems using &#x3b2;-lactamase as a reporter gene also are disclosed.

Substrates for beta-lactamase and uses thereof

Substrates for &#x3b2;-lactamase of the general formula I in which one of X and Y is a fluorescent donor moiety and the other is a quencher (which may or may not re-emit); R' is selected from the group consisting of H, lower (i.e., alkyl of 1 to about 5 carbon atoms) and (CH)OH, in which n is 0 or an integer from 1 to 5; R&#x2033; is selected from the group consisting of H, physiologically acceptable metal and ammonium cations, &#x2014;CHROCO(CH)CH, &#x2014;CHROCOC(CH), acylthiomethyl, acyloxy-alpha-benzyl, delta-butyrolactonyl, methoxycarbonyloxymethyl, phenyl, methylsulphinylmethyl, beta-morpholinoethyl, dialkylaminoethyl, acyloxyalkyl, dialkylaminocarbonyloxymethyl and aliphatic, in which Ris selected from the group consisting of H and lower alkyl; A is selected from the group consisting of S, O, SO, SOand CH; and Z&#x2032; and Z&#x2033; are linkers for the fluorescent donor and quencher moieties. Methods of assaying &#x3b2;-lactamase activity and monitoring expression in systems using &#x3b2;-lactamase as a reporter gene also are disclosed.

Substrates for &#x3b2;-lactamase and uses thereof

The invention provides methods of using an optical molecular probe or sensor to screen candidate drugs for their interaction with at least one cytochrome P450 enzyme. The optical molecular probe useful in the methods of the present invention is a compound having the generic structure Y-L-Q, wherein Y is selected from the group consisting of Q as herein defined, saturated C&#x2013;Calkyl, unsaturated C&#x2013;Calkenyl, unsaturated C&#x2013;Calkynyl, substituted saturated C&#x2013;Calkyl, substituted unsaturated C&#x2013;Calkenyl, substituted unsaturated C&#x2013;Calkynyl, C&#x2013;Ccycloalkyl, C&#x2013;Ccycloalkenyl, substituted saturated C&#x2013;Ccycloalkyl, substituted unsaturated C&#x2013;Ccycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; L is selected from the group of (&#x2014;OCRH)&#x2014;, wherein for each p, all Rare separately selected from the group consisting of a hydrogen atom, saturated C&#x2013;Calkyl, unsaturated C&#x2013;Calkenyl, unsaturated C&#x2013;Calkynyl, substituted saturated C&#x2013;Calkyl, substituted unsaturated C&#x2013;Calkenyl, substituted unsaturated C&#x2013;Calkynyl, C&#x2013;Ccycloalkyl, C&#x2013;Ccycloalkenyl, substituted saturated C&#x2013;Ccycloalkyl, substituted unsaturated C&#x2013;Ccycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and p is a positive integer no greater than twelve; and Q is a chemical moiety that gives rise to optical properties in its hydroxy or hyrdoxylate, phenol or phenoxide form that are different from the optical properties that arise from its ether form. Most preferably, p is one, Ris hydrogen, and Q is the ether form of a phenoxide fluorophore.

Methods for detecting the interaction of compounds with cytochrome P450 using optical molecular sensors

The present invention provides a method for reducing undesirable light emission from a sample using at least one photon producing agent and at least one photon reducing agent (e.g. dye-based photon reducing agents). The present invention further provides a method for reducing undesirable light emission from a sample (e.g., a biochemical or cellular sample) with at least one photon producing agent and at least one collisional quencher. The present invention also provides a method for reducing undesirable light emission from a sample (e.g., a biochemical or cellular sample) with at least one photon producing agent and at least one quencher, such as an electronic quencher. The present invention also provides a system and method of screening test chemicals in fluorescent assays using photon reducing agents. The present invention also provides compositions, pharmaceutical compositions, and kits for practicing these methods.

Photon reducing agents for fluorescence assays

The invention provides methods of using a compound as an optical probe or sensor of the activity of at least one cytochrome P450 enzyme, and methods of using the compound to screen candidate drugs, and kits for performing these methods. The optical probe of the invention is a compound having the generic structure Y-L-Q, wherein Y is selected from the group consisting of Q as herein defined, saturated C -C alkyl, unsaturated C -C alkenyl, unsaturated C -C alkynyl, substituted saturated C -C alkyl, substituted unsaturated C -C alkenyl, substituted unsaturated C -C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, substituted saturated C -C cycloalkyl, substituted unsaturated C -C cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; L is selected from the group of (&mdash;OCR H) &mdash;, wherein for each p, all R are separately selected from the group consisting of a hydrogen atom, saturated C -C alkyl, unsaturated C -C alkenyl, unsaturated C -C alkynyl, substituted saturated C -C alkyl, substituted unsaturated C -C alkenyl, substituted unsaturated C -C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, substituted saturated C -C cycloalkyl, substituted unsaturated C -C cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and p is a positive integer no greater than twelve; and Q is a chemical moiety that gives rise to optical properties in its hydroxy or hyrdoxylate, phenol or phenoxide form that are different from the optical properties that arise from its ether form. Most preferably, p is one, R is hydrogen, and Q is the ether form of a phenoxide fluorophore.

The invention provides a compound, useful as an optical probe or sensor of the activity of at least one cytochrome P450 enzyme, and methods of using the compound to screen candidate drugs, and candidate drugs identified by these methods. The optical probe of the invention is a compound having the generic structure Y&mdash;L&mdash;Q, wherein Y is selected from the group consisting of Q as herein defined, saturated C -C alkyl, unsaturated C -C alkenyl, unsaturated C -C alkynyl, substituted saturated C -C alkyl, substituted unsaturated C -C alkenyl, substituted unsaturated C -C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, substituted saturated C -C cycloalkyl, substituted unsaturated C -C cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; L is selected from the group of (&mdash;OCR H) &mdash;, wherein for each p, all R are separately selected from the group consisting of a hydrogen atom, saturated C -C alkyl, unsaturated C -C alkenyl, unsaturated C -C alkynyl, substituted saturated C -C alkyl, substituted unsaturated C -C alkenyl, substituted unsaturated C -C alkynyl, C -C cycloalkyl, C -C cycloalkenyl, substituted saturated C -C cycloalkyl, substituted unsaturated C -C cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and p is a positive integer no greater than twelve; and Q is a chemical moiety that gives rise to optical properties in its hydroxy or hyrdoxylate, phenol or phenoxide form that are different from the optical properties that arise from its ether form. Most preferably, p is one, R is hydrogen, and Q is the ether form of a phenoxide fluorophore.

Growing community of inventors

La Jolla, CA, United States of America

Gregor Zlokarnik