- POLYCYCLIC AMINES AS OPIOID RECEPTOR MODULATORS
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The present invention provides a genus of polycyclic amines that are useful as opioid receptor modulators. The compounds of the invention are useful in both therapeutic and diagnostic methods, including for treating pain, neurological disorders, cardiac disorders, bowel disorders, drug and alcohol addiction, drug overdose, urinary disorders, respiratory disorders, sexual dysfunction, psoriasis, graft rejection or cancer.
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Paragraph 0129; 0191
(2018/10/11)
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- N-LINKED LACTAM M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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The present invention is directed to N-linked lactam compounds of general formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
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Page/Page column 41
(2012/12/13)
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- Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold
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One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M1 muscarinic receptor. A number of nonselective M1 muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M2 to M5 subtypes. One strategy to confer selectivity for M1 is the identification of positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M1 positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
- Kuduk, Scott D.,Chang, Ronald K.,Di Marco, Christina N.,Pitts, Daniel R.,Greshock, Thomas J.,Ma, Lei,Wittmann, Marion,Seager, Matthew A.,Koeplinger, Kenneth A.,Thompson, Charles D.,Hartman, George D.,Bilodeau, Mark T.,Ray, William J.
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experimental part
p. 4773 - 4780
(2011/09/20)
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- AMINOBENZOQUINAZOLINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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The present invention is directed to aminobenzoquinazolinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor
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Page/Page column 33-34
(2011/08/03)
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- Preparation of 4-heteroaryl-4-cyanopiperidines via SNAr substitution reactions
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The scope and limitations of SNAr substitution reactions of metalated 4-cyanopiperidines with heterocyclic halides were explored. These facile reactions provide rapid access to a wide range of 4-heteroaryl-4-cyanopiperidines and have resulted i
- Chang, Ronald K.,Di Marco, Christina N.,Pitts, Daniel R.,Greshock, Thomas J.,Kuduk, Scott D.
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experimental part
p. 6303 - 6306
(2010/01/18)
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- QUINOLIZIDINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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The present invention is directed to spiropiperidine compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
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Page/Page column 25-26
(2009/05/28)
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- Discovery of N-{[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]methyl}benzamides as novel, selective and potent GlyT1 inhibitors
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Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues.
- Zhao, Zhijian,Leister, William H.,O'Brien, Julie A.,Lemaire, Wei,Williams Jr., David L.,Jacobson, Marlene A.,Sur, Cyrille,Kinney, Gene G.,Pettibone, Doug J.,Tiller, Philip R.,Smith, Sheri,Hartman, George D.,Lindsley, Craig W.,Wolkenberg, Scott E.
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scheme or table
p. 1488 - 1491
(2009/11/30)
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- Discovery of GlyT1 inhibitors with improved pharmacokinetic properties
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Glycine transporter 1 (GlyT1) represents a novel target for the treatment of schizophrenia via the potentiation of glutamatergic NMDA receptors. The discovery of 4,4-disubstituted piperidine inhibitors of GlyT1 which exhibit improved pharmacokinetic prope
- Wolkenberg, Scott E.,Zhao, Zhijian,Wisnoski, David D.,Leister, William H.,O'Brien, Julie,Lemaire, Wei,Williams Jr., David L.,Jacobson, Marlene A.,Sur, Cyrille,Kinney, Gene G.,Pettibone, Doug J.,Tiller, Philip R.,Smith, Sheri,Gibson, Christopher,Ma, Bennett K.,Polsky-Fisher, Stacey L.,Lindsley, Craig W.,Hartman, George D.
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scheme or table
p. 1492 - 1495
(2009/11/30)
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- RADIOLABELED GLYCINE TRANSPORTER INHIBITORS
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The present invention is directed to radiolabeled glycine transporter inhibitors which are useful for the labeling and diagnostic imaging of glycine transporters in mammals.
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Page/Page column 19
(2008/06/13)
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- Heteroaryl Piperidine Glycine Transporter Inhibitors
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The present invention is directed to pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl piperidine compounds that inhibit the glycine transporter GlyT1 and which are useful in the treatment of neurological and psychiatric disorders associated with glycinergi
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Page/Page column 15; 17
(2010/11/28)
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- E-FLUORO-4-(PYRIDIN-2-YL)-PIPERIDINE-1-CARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS WHICH MODULATE THE FUNCTION OF THE VANILLOID-1 RECEPTOR (VR1) FOR THE TREATMENT OF PAIN
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Compounds of formula (I): wherein: A1 is phenyl, a six-membered aromatic heterocycle containing one, two or three nitrogen atoms, or a five-membered aromatic heterocycle containing up to four heteroatoms chosen from O, N and S, at most one hete
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Page/Page column 28
(2010/02/11)
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- Selective alpha1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-ones.
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A series of alpha1a receptor antagonists derived from a 4-aryl-3,4-dihydropyridine-2-one heterocycle is disclosed. Potency in the low nanomolar to picomolar range along with high selectivity was obtained. In vivo efficacy in a prostate contraction model in rats was observed with a few derivatives.
- Nantermet,Barrow,Selnick,Homnick,Freidinger,Chang,O'Malley,Reiss,Broten,Ransom,Pettibone,Olah,Forray
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p. 1625 - 1628
(2007/10/03)
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- SUBSTITUTED PYRROLIDIN-3-YL-ALKYL-PIPERIDINES
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The present invention relates to substituted pyrrolidinyl-3-yl-alkyl-piperidines, their stereoisomers, and pharmaceutically acceptable salts thereof and processes for preparation of the same. The compounds of the present invention are useful in their pharmacological activities such as tachykinin antagonism, especially substance P and neurokinin A antagonism, and the like. Compounds having the property of tachykinin antagonism are indicated for conditions associated with neurogenic inflammation and other diseases described herein.
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