Methods of diagnosing, monitoring and treating pulmonary diseases
The invention includes methods of discriminating asthma from obstructive pulmonary disease, of treating pulmonary diseases, of treating cough, of assessing the efficacy of a treatment for an obstructive pulmonary disease, and of inhibiting activation of a P2-purinoreceptor (P2R).
1 . A method of diagnosis, the method comprising:
(a) identifying a test subject suspected of having asthma or chronic pulmonary obstructive disease (COPD);
(b) administering a provocator compound to the subject;
(c) determining a difference in lung function between before and after the administration;
(d) determining whether the difference in lung function more closely resembles the difference in the lung function in control subjects having (i) asthma or (ii) COPD; and
(e) classifying the test subject as: (1) likely to have asthma if the difference in lung function in the test subject more closely resembles the difference in lung function in control subjects having asthma than the difference in lung function in control subjects having COPD ; or (2) likely to have COPD if the difference in lung function in the test subject more closely resembles the difference in lung function in control subjects having COPD than the difference in lung function in control subjects having asthma.
2 . The method of claim 1 , wherein the difference in lung function is determined as a function of the amount of the provocator compound that is required to cause an arbitrary particular decrease in forced expiratory volume (FEV 1 ).
3 . The method of claim 2 , wherein the arbitrary particular decrease is a decrease of about 20%.
4 . The method of claim 1 , wherein the difference in lung function is determined as a function of the amount of provocator compound that is required to cause an arbitrary particular change in the specific airway conductance (sGaw), Borg score, functional residual capacity (FRC), forced expiratory flow (FEF) or peak expiratory flow rate (PEFR).
5 . The method of claim 4 , wherein the arbitrary particular change is a decrease or increase of greater than about 10%.
6 . The method of claim 1 , wherein the provocator compound is adenosine 5′-triphosphate (ATP).
7 . The method of claim 1 , wherein the provocator compound is an analog of ATP.
8 . The method of claim 7 , wherein the analog of ATP is α,β-methylene ATP (αβmATP).
9 . The method of claim 7 , wherein the analog of ATP is β,γ-methylene ATP (β,γmATP).
10 . The method of claim 1 , wherein the provocator compound is di-adenosine pentaphosphate (Ap 5 A).
11 . The method of claim 1 , wherein the administration is by intrapulmonary inhalation.
12 . The method of claim 1 , wherein the administration is by intravenous bolus injection.
13 . A method of therapy, the method comprising:
(a) performing the method of claim 1; and
(b) treating the test subject for asthma or COPD.
14 . A method of assessing the efficacy of treatment for asthma or COPD, the method comprising:
(a) performing the method of claim 13;
(b) administering a provocator compound to the test subject;
(c) determining a difference in lung function, or detecting a change in at least one symptom, between before and after the administration;
(d) determining whether the difference in lung function, or the change in the at least one symptom, in the test subject is closer to a mean change in lung function, or a mean difference in the at least one symptom, in control normal subjects than the difference in lung function, or in the change in the at least one symptom, in the test subject determined or detected prior to the treatment of claim 13; and
(e) classifying the treatment as effective if the difference in lung function, or the change in the at least symptom, in the test subject is closer to the mean change in lung function, or mean difference in the at least one symptom, in control normal subjects than a difference in lung function, or in a change in the at least one symptom, in the test subject determined or detected prior to the treatment of claim 13 .
15 . A method of assessing the efficacy of treatment for an obstructive lung disease (OPD), the method comprising:
(a) identifying a subject that has been treated for an OPD;
(b) administering a provocator compound to the test subject;
(c) determining a difference in lung function, or detecting a change in at least one symptom, between before and after the administration;
(d) determining whether the difference in lung function, or the change in the at least one symptom, in the test subject is closer to the mean change in lung function, or mean difference in at least one symptom, in control normal subjects than the difference in lung function, or in the change in the at least one symptom, in the test subject determined or detected prior to the treatment for the OPD; and
(e) classifying the treatment as effective if the difference in lung function, or the change in at least one symptom, in the test subject is closer to the mean change in lung function, or mean difference in at least one symptom, in control normal subjects than the difference in lung function, or in the change in the at least one symptom, in the test subject determined or detected prior to the treatment.
16 . A method of treating an OPD or cough, the method comprising:
(a) identifying a mammalian subject as having an OPD, having symptoms associated with an OPD, or having cough;
(b) administering to the subject a therapeutically effective dose of a pharmaceutical composition that comprises one or more compounds, each compound being of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
A 1 and A 2 are each independently selected from the group consisting of alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NR A R B )carbonyl, —NR C S(O) 2 R D , —S(O) 2 OH, and tetrazolyl; or
A 1 and A 2 together with the carbon atoms to which they are attached form a five membered heterocycle containing a sulfur atom wherein the five membered heterocycle is optionally substituted with 1 or 2 substituents selected from mercapto and oxo;
A 3 is selected from the group consisting of alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NR A R B )carbonyl, NR C S(O) 2 R D , —S(O) 2 OH, and tetrazolyl;
A 4 , A 5 , A 6 and A 7 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, —NR E R F , and (NR E R F )carbonyl;
A 8 , A 9 , A 10 and A 11 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, —NR E R F , (NR E R F )carbonyl, and oxo;
R A and R B are each independently selected from the group consisting of hydrogen, alkyl, and cyano;
R C is selected from the group consisting of hydrogen and alkyl;
R D is selected from the group consisting of alkoxy, alkyl, aryl, arylalkoxy, arylalkyl, haloalkoxy, and haloalkyl;
R E and R F are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, formyl, and hydroxyalkyl;
L 1 is selected from the group consisting of alkenylene, alkylene, alkynylene, —(CH 2 ) m O(CH 2 ) n —, —(CH 2 ) m S(CH 2 ) n —, and —(CH 2 ) p C(O)(CH 2 ) q —, wherein the left end of the group is attached to N and the right end of the group is attached to R 1 ;
m is an integer 0-10;
n is an integer 0-10;
R 1 is selected from the group consisting of aryl, cycloalkenyl, cycloalkyl, and heterocycle;
L 2 is absent or selected from the group consisting of a covalent bond, alkenylene, alkylene, alkynylene, —(CH 2 ) p O(CH 2 ) q —, —(CH 2 ) p S(CH 2 ) q —, —(CH 2 ) p C(O)(CH 2 ) q —, —(CH 2 ) p C(OH)(CH 2 ) q —, and —(CH 2 ) p CH═NO(CH 2 ) q —, wherein the left end of the group is attached to R 1 and the right end of the group is attached to R 2 ;
p is an integer 0-10;
q is an integer 0-10; and
R 2 is absent or selected from the group consisting of aryl, cycloalkenyl, cycloalkyl, and heterocycle.
17 . The method of claim 16 , wherein the compound is 5-({(3-phenoxybenzyl)[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino}carbonyl)-1,2,4-benzenetricarboxylic acid (A-317491).
18 . The method of claim 16 , wherein the OPD is chronic obstructive pulmonary disease (COPD).
19 . The method of claim 16 , wherein the OPD comprises coughing.
20 . The method of claim 16 , wherein the OPD is asthma.
21 . The method of claim 16 , wherein the OPD is selected from the group consisting of acute bronchitis, emphysema, chronic bronchitis, bronchiectasis, cystic fibrosis, and acute asthma.
22 . The method of claim 16 , wherein the compound has the ability to inhibit a vagal response mediated by a P2R on a vagal afferent nerve terminal.
23 . The method of claim 22 , wherein the P2R is a P2X receptor.
24 . The method of claim 23 , wherein the P2X receptor is a P2X 3 receptor.
25 . The method of claim 23 , wherein the P2X receptor is a P2X 2/3 receptor.
26 . The method of claim 16 , wherein the administration of the composition is by intrapulmonary inhalation.
27 . The method of claim 16 , wherein the administration of the composition is by intravenous bolus injection.
28 . A method of inhibiting activation of a P2R on a pulmonary vagal sensory nerve fiber terminal, the method comprising contacting the vagal sensory nerve fiber terminal with one or more compounds, each compound being of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
A 1 and A 2 are each independently selected from the group consisting of alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NR A R B )carbonyl, —NR C S(O) 2 R D , —S(O) 2 OH, and tetrazolyl; or
A 1 and A 2 together with the carbon atoms to which they are attached form a five membered heterocycle containing a sulfur atom wherein the five membered heterocycle is optionally substituted with 1 or 2 substituents selected from mercapto and oxo;
A 3 is selected from the group consisting of alkoxycarbonyl, alkylcarbonyloxy, carboxy, hydroxy, hydroxyalkyl, (NR A R B )carbonyl, NR C S(O) 2 R D , —S(O) 2 OH, and tetrazolyl;
A 4 , A 5 , A 6 and A 7 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, —NR E R F , and (NR E R F )carbonyl;
A 8 , A 9 , A 10 and A 11 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkenyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkynyl, aryl, carboxy, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, —NR E R F , (NR E R F )carbonyl, and oxo;
R A and R B are each independently selected from the group consisting of hydrogen, alkyl, and cyano;
R C is selected from the group consisting of hydrogen and alkyl;
R D is selected from the group consisting of alkoxy, alkyl, aryl, arylalkoxy, arylalkyl, haloalkoxy, and haloalkyl;
R E and R F are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, formyl, and hydroxyalkyl;
L 1 is selected from the group consisting of alkenylene, alkylene, alkynylene, —(CH 2 ) m O(CH 2 ) n —, —(CH 2 ) m S(CH 2 ) n —, and —(CH 2 ) p C(O)(CH 2 ) q —, wherein the left end of the group is attached to N and the right end of the group is attached to R 1 ;
m is an integer 0-10;
n is an integer 0-10;
R 1 is selected from the group consisting of aryl, cycloalkenyl, cycloalkyl, and heterocycle;
L 2 is absent or selected from the group consisting of a covalent bond, alkenylene, alkylene, alkynylene, —(CH 2 ) p O(CH 2 ) q —, —(CH 2 ) p S(CH 2 ) q —, (CH 2 ) p C(O)(CH 2 ) q —, —(CH 2 ) p C(OH)(CH 2 ) q —, and (CH 2 ) p CH═NO(CH 2 ) q —, wherein the left end of the group is attached to R 1 and the right end of the group is attached to R 2 ;
p is an integer 0-10;
q is an integer 0-10; and
R 2 is absent or selected from the group consisting of aryl, cycloalkenyl, cycloalkyl, and heterocycle.