Richard Heier - Academia.edu (original) (raw)
Papers by Richard Heier
Journal of Pharmacy and Pharmacology, 1991
... a-Methyl analogues of acetylenic amines as striatal muscarinic antagonists VIMALA H. SETHY,RI... more ... a-Methyl analogues of acetylenic amines as striatal muscarinic antagonists VIMALA H. SETHY,RICHARD F. HEIER. ... References Bebbington. A,, Brimblecombe, R. W., Shakeshaft, D. (1966) Thc central and peripheral activity of acetylenic amines related to oxotremorine. Br. ...
The Journal of Organic Chemistry, 1998
PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evalution as a chemothera... more PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evalution as a chemotherapeutic agent for treatment of AIDS, was synthesized by a convergent approach amenable to large-scale preparation in a pilot plant environment. The key step is the aldol addition of nitroaromatic ester (+)-8 to aldehyde 19e. The two stereocenters present in the target molecule were each set independently by resolution of enantiomers. Intermediates along the synthetic routes were chosen to maximize opportunities for isolation and purification by crystallization.
Journal of Labelled Compounds and Radiopharmaceuticals, 1996
ABSTRACT (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (1) is a dopamine... more ABSTRACT (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (1) is a dopamine agonist which shows selectivity for the D2 receptor subtype, and is of interest as a potential drug for the treatment of Parkinson's disease. An asymmetric epoxidation approach has been used to prepare 1 in eleven steps (15% overall yield) from 8-nitroquinoline. An advanced intermediate in this synthesis, tert-butyl (R)-methyl(8-amino-1,2,3,4-tetrahydro-3-quinolinyl)carbamate (10), has been reacted with [14C]phosgene to provide a two-step synthesis of 1 labeled with carbon-14 at the C-2 position (236 μCi/mg). Bromination of 1 gave the dibromo analogue 12b which was reduced in the presence of tritium gas to give 1 labeled with tritium at the C-6 and C-7 positions (28.5 Ci/mmol). In addition to providing syntheses for labeled forms of the drug which are useful in drug disposition and receptor binding studies, this approach also provides a convenient synthesis for the unlabeled form of drug.
J Med Chem, 1992
The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a pot... more The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
Journal of Medicinal Chemistry, 1991
A series of acetylenic imidazoles related to oxotremorine (1a) were prepared and evaluated as cho... more A series of acetylenic imidazoles related to oxotremorine (1a) were prepared and evaluated as cholinergic agents with in vitro binding assays and in vivo pharmacological tests in mice. 1-[4-(1H-Imidazol-1-yl)-2-butynyl]-2-pyrrolidinone (1b) was a cholinergic agonist with one-half the potency of oxotremorine. Analogues of 1b with a 5- or 2-methyl substituent in the imidazole ring (compounds 1c and 1g) were cholinergic partial agonists. Analogues of 1b with a methyl substituent at the 5-position in the pyrrolidinone ring (7b) or at the alpha-position in the acetylenic chain (8b) were antagonists. Various analogues of these imidazole acetylenes where the pyrrolidinone ring was replaced by an amide, carbamate, or urea residue were prepared. Several compounds which contained 5-methylimidazole as the amine substituent were partial agonists. The activities of the imidazole compounds are compared with those of the related pyrrolidine and dimethylamine analogues. Agonist and antagonist conformations for these compounds at muscarinic receptors are proposed.
Journal of Medicinal Chemistry, 1992
The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a pot... more The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
Journal of Medicinal Chemistry, 1997
The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is... more The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
Journal of Clinical Investigation, 2012
Increased mucus production is a common cause of morbidity and mortality in inflammatory airway di... more Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.
Drug Development Research, 1991
Moon: U-80816: A novel partial muscarinic agonist. Drug Dev. Res. 2453-66, 1991. U-80816 (1 -(4-(... more Moon: U-80816: A novel partial muscarinic agonist. Drug Dev. Res. 2453-66, 1991. U-80816 (1 -(4-(5-methyI-l H-imidazol-1 -yl)-2-butynyl)-2-pyrrolidinone is an acetylenic amine which has been investigated as a partial agonist of muscarinic receptors. In vitro U-80816 inhibited binding of (3H)-N-methylscopolamine [(3H)-NMS] and (methyL3H) oxotremorine-M acetate [(3H:l-Oxo-M] to the cortical membrane preparation with Ki's of 75 and 3.24 nM, respectively. In the M1 cell line, U-80816 increased phosphatidylinositol (PI)
Biophysical Journal, 2013
J. Med. …, 1997
The imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is... more The imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, ...
Bioorganic & Medicinal Chemistry, 2011
Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK... more Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Journal of Pharmacy and Pharmacology, 1991
... a-Methyl analogues of acetylenic amines as striatal muscarinic antagonists VIMALA H. SETHY,RI... more ... a-Methyl analogues of acetylenic amines as striatal muscarinic antagonists VIMALA H. SETHY,RICHARD F. HEIER. ... References Bebbington. A,, Brimblecombe, R. W., Shakeshaft, D. (1966) Thc central and peripheral activity of acetylenic amines related to oxotremorine. Br. ...
The Journal of Organic Chemistry, 1998
PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evalution as a chemothera... more PNU-140690, an inhibitor of the HIV protease enzyme undergoing clinical evalution as a chemotherapeutic agent for treatment of AIDS, was synthesized by a convergent approach amenable to large-scale preparation in a pilot plant environment. The key step is the aldol addition of nitroaromatic ester (+)-8 to aldehyde 19e. The two stereocenters present in the target molecule were each set independently by resolution of enantiomers. Intermediates along the synthetic routes were chosen to maximize opportunities for isolation and purification by crystallization.
Journal of Labelled Compounds and Radiopharmaceuticals, 1996
ABSTRACT (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (1) is a dopamine... more ABSTRACT (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (1) is a dopamine agonist which shows selectivity for the D2 receptor subtype, and is of interest as a potential drug for the treatment of Parkinson's disease. An asymmetric epoxidation approach has been used to prepare 1 in eleven steps (15% overall yield) from 8-nitroquinoline. An advanced intermediate in this synthesis, tert-butyl (R)-methyl(8-amino-1,2,3,4-tetrahydro-3-quinolinyl)carbamate (10), has been reacted with [14C]phosgene to provide a two-step synthesis of 1 labeled with carbon-14 at the C-2 position (236 μCi/mg). Bromination of 1 gave the dibromo analogue 12b which was reduced in the presence of tritium gas to give 1 labeled with tritium at the C-6 and C-7 positions (28.5 Ci/mmol). In addition to providing syntheses for labeled forms of the drug which are useful in drug disposition and receptor binding studies, this approach also provides a convenient synthesis for the unlabeled form of drug.
J Med Chem, 1992
The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a pot... more The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
Journal of Medicinal Chemistry, 1991
A series of acetylenic imidazoles related to oxotremorine (1a) were prepared and evaluated as cho... more A series of acetylenic imidazoles related to oxotremorine (1a) were prepared and evaluated as cholinergic agents with in vitro binding assays and in vivo pharmacological tests in mice. 1-[4-(1H-Imidazol-1-yl)-2-butynyl]-2-pyrrolidinone (1b) was a cholinergic agonist with one-half the potency of oxotremorine. Analogues of 1b with a 5- or 2-methyl substituent in the imidazole ring (compounds 1c and 1g) were cholinergic partial agonists. Analogues of 1b with a methyl substituent at the 5-position in the pyrrolidinone ring (7b) or at the alpha-position in the acetylenic chain (8b) were antagonists. Various analogues of these imidazole acetylenes where the pyrrolidinone ring was replaced by an amide, carbamate, or urea residue were prepared. Several compounds which contained 5-methylimidazole as the amine substituent were partial agonists. The activities of the imidazole compounds are compared with those of the related pyrrolidine and dimethylamine analogues. Agonist and antagonist conformations for these compounds at muscarinic receptors are proposed.
Journal of Medicinal Chemistry, 1992
The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a pot... more The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
Journal of Medicinal Chemistry, 1997
The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is... more The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
Journal of Clinical Investigation, 2012
Increased mucus production is a common cause of morbidity and mortality in inflammatory airway di... more Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.
Drug Development Research, 1991
Moon: U-80816: A novel partial muscarinic agonist. Drug Dev. Res. 2453-66, 1991. U-80816 (1 -(4-(... more Moon: U-80816: A novel partial muscarinic agonist. Drug Dev. Res. 2453-66, 1991. U-80816 (1 -(4-(5-methyI-l H-imidazol-1 -yl)-2-butynyl)-2-pyrrolidinone is an acetylenic amine which has been investigated as a partial agonist of muscarinic receptors. In vitro U-80816 inhibited binding of (3H)-N-methylscopolamine [(3H)-NMS] and (methyL3H) oxotremorine-M acetate [(3H:l-Oxo-M] to the cortical membrane preparation with Ki's of 75 and 3.24 nM, respectively. In the M1 cell line, U-80816 increased phosphatidylinositol (PI)
Biophysical Journal, 2013
J. Med. …, 1997
The imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is... more The imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, ...
Bioorganic & Medicinal Chemistry, 2011
Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK... more Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).