Discovery of Novel, Potent, Brain-Permeable, and Orally Efficacious Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptor [4-(5-(4-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide]: Structure-Activity Relationship and Preclinical Characterization

被引：19

作者：

Sinha, Neelima ^{[1
]}

Karche, Navnath P. ^{[1
]}

Verma, Mahip Kalyan ^{[1
]}

Walunj, Sameer S. ^{[1
]}

Nigade, Prashant B. ^{[1
]}

Jana, Gourhari ^{[1
]}

Kurhade, Sanjay P. ^{[1
]}

Hajare, Anil K. ^{[1
]}

Tilekar, Ajay R. ^{[1
]}

Jadhav, Ganesh R. ^{[1
]}

Thube, Baban R. ^{[1
]}

Shaikh, Javed S. ^{[1
]}

Balgude, Sudhakar ^{[1
]}

Singh, Lairikyengbam Bikramjit ^{[1
]}

Mahimane, Vijaya ^{[1
]}

Adurkar, Shridhar K. ^{[1
]}

Hatnapure, Girish ^{[1
]}

Raje, Firoj ^{[1
]}

Bhosale, Yogesh ^{[1
]}

Bhanage, Dnyaneshwar ^{[1
]}

Sachchidanand, Sachchidanand ^{[1
]}

Dixit, Ruchi ^{[1
]}

Gupta, Rajesh ^{[1
]}

Bokare, Anand M. ^{[1
]}

Dandekar, Manoj ^{[1
]}

Bharne, Ashish ^{[1
]}

Chatterjee, Manavi ^{[1
]}

Desai, Sagar ^{[1
]}

Koul, Sarita ^{[1
]}

Modi, Dipak ^{[1
]}

Mehta, Maneesh ^{[1
]}

Patil, Vinod ^{[1
]}

Singh, Minakshi ^{[1
]}

Gundu, Jayasagar ^{[1
]}

Goel, Rajan N. ^{[1
]}

Shah, Chirag ^{[1
]}

Sharma, Sharad ^{[1
]}

Bakhle, Dhananjay ^{[1
]}

Kamboj, Rajender Kumar ^{[1
]}

Palle, Venkata P. ^{[1
]}

机构：

[1] Lupin Ltd, Lupin Res Pk, Novel Drug Discovery & Dev, Survey 46 A-47 A, Pune 412115, Maharashtra, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 03期

关键词：

COGNITIVE IMPAIRMENT; PARTIAL AGONIST; SCHIZOPHRENIA; TRANSMISSION; SELECTIVITY; ACTIVATION; EVP-6124; RODENTS; SAFETY; MEMORY;

D O I：

10.1021/acs.jmedchem.9b01569

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of a series of thiophenephenyl-sulfonamides as positive allosteric modulators (PAM) of alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.

引用

页码：944 / 960

页数：17

共 45 条

[31] Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor
Chen, Chen
Wu, Dongpei
Guo, Zhiqiang
Xie, Qiu
Reinhart, Greg J.
Madan, Ajay
Wen, Jenny
Chen, Takung
Huang, Charles Q.
Chen, Mi
Chen, Yongsheng
Tucci, Fabio C.
Rowbottom, Martin
Pontillo, Joseph
Zhu, Yun-Fei
Wade, Warren
Saunders, John
Bozigian, Haig
Struthers, R. Scott
JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (23) : 7478 - 7485
[32] Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity
Lin, Linus S.
Lanza, Thomas J., Jr.
Jewell, James P.
Liu, Ping
Shah, Shrenik K.
Qi, Hongbo
Tong, Xinchun
Wang, Junying
Xu, Suoyu S.
Fong, Tung M.
Shen, Chun-Pyn
Lao, Julie
Xiao, Jing Chen
Shearman, Lauren P.
Stribling, D. Sloan
Rosko, Kimberly
Strack, Alison
Marsh, Donald J.
Feng, Yue
Kumar, Sanjeev
Samuel, Koppara
Yin, Wenji
Van der Ploeg, Lex H. T.
Goulet, Mark T.
Hagmann, William K.
JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (26) : 7584 - 7587
[33] Discovery of N-[(4R)-6-(4-Chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596) as a Novel Cannabinoid-1 Receptor (CB1R) Inverse Agonist for the Treatment of Obesity
Yan, Lin
Huo, Pei
Debenham, John S.
Madsen-Duggan, Christina B.
Lao, Julie
Chen, Richard Z.
Xiao, Jing Chen
Shen, Chun-Pyn
Stribling, D. Sloan
Shearman, Lauren P.
Strack, Alison M.
Tsou, Nancy
Ball, Richard G.
Wang, Junying
Tong, Xinchun
Bateman, Thomas J.
Reddy, Vijay B. G.
Fong, Tung M.
Hale, Jeffrey J.
JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (10) : 4028 - 4037
[34] Structure-Activity Relationship Studies Leading to the Identification of (2E)-3-[1-[2,4-Dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl]-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041), a Potent and Selective Prostanoid EP3 Receptor Antagonist, as a Novel Antiplatelet Agent That Does Not Prolong Bleeding
Singh, Jasbir
Zeller, Wayne
Zhou, Nian
Hategan, Georgeta
Mishra, Rama K.
Polozov, Alex
Yu, Peng
Onua, Emmanuel
Zhang, Jun
Ramirez, Jose L.
Sigthorsson, Gudmundur
Thorsteinnsdottir, Margret
Kiselyov, Alex. S.
Zembower, David E.
Andresson, Thorkell
Gurney, Mark E.
JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (01) : 18 - 36
[35] STRUCTURE-ACTIVITY RELATIONSHIP OF N-[2-(DIMETHYLAMINO)-6-[3-(5-METHYL-4-PHENYL-1H-IMIDAZOL-1-YL)PROPOXY]PHENYL]-N'-PENTYLUREA AND ANALOGS - NOVEL POTENT INHIBITORS OF ACYL-COA CHOLESTEROL O-ACYLTRANSFERASE WITH ANTIATHEROSCLEROTIC ACTIVITY
KIMURA, T
TAKASE, Y
HAYASHI, K
TANAKA, H
OHTSUKA, I
SAEKI, T
KOGUSHI, M
YAMADA, T
FUJIMORI, T
SAITOU, I
AKASAKA, K
JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (11) : 1630 - 1640
[36] Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer
El-Ahmad, Youssef
Tabart, Michel
Halley, Frank
Certal, Victor
Thompson, Fabienne
Filoche-Romme, Bruno
Gruss-Leleu, Florence
Muller, Claire
Brollo, Maurice
Fabien, Laurence
Loyau, Veronique
Bertin, Luc
Richepin, Patrick
Pilorge, Fabienne
Desmazeau, Pascal
Girardet, Chrystelle
Beccari, Sylvie
Louboutin, Audrey
Lebourg, Gilles
Le -Roux, Jacques
Terrier, Corinne
Vallee, Francois
Steier, Valerie
Mathieu, Magali
Rak, Alexey
Abecassis, Pierre-Yves
Vicat, Pascale
Benard, Tsiala
Bouaboula, Monsif
Sun, Fangxian
Shomali, Maysoun
Hebert, Andrew
Levit, Mikhail
Cheng, Hong
Courjaud, Albane
Ginesty, Celine
Perrault, Christelle
Garcia-Echeverria, Carlos
McCort, Gary
Schiot, Laurent
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (02) : 512 - 528
[37] Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent
Wang, Bing
Chu, Daniel
Feng, Ying
Shen, Yuqiao
Aoyagi-Scharber, Mika
Post, Leonard E.
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (01) : 335 - 357
[38] Novel Non-Peptide Nociceptin/Orphanin FQ Receptor Agonist, 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: Design, Synthesis, and Structure-Activity Relationship of Oral Receptor Occupancy in the Brain for Orally Potent Antianxiety Drug
Hayashi, Shigeo
Hirao, Akiko
Imai, Aki
Nakamura, Hiroshi
Murata, Yoshinori
Ohashi, Katsuyo
Nakata, Eriko
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (03) : 610 - 625
[39] Structure-Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4-[3-Chloro-5-[(1S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management
Tafesse, Laykea
Kanemasa, Toshiyuki
Kurose, Noriyuki
Yu, Jianming
Asaki, Toshiyuki
Wu, Gang
Iwamoto, Yuka
Yamaguchi, Yoshitaka
Ni, Chiyou
Engel, John
Tsuno, Naoki
Patel, Aniket
Zhou, Xiaoming
Shintani, Takuya
Brown, Kevin
Hasegawa, Tsuyoshi
Shet, Manjunath
Iso, Yasuyoshi
Kato, Akira
Kyle, Donald J.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (15) : 6781 - 6794
[40] Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: Design, synthesis, and structure-activity relationships
Hayashi, Shigeo
Nakata, Eriko
Morita, Asato
Mizuno, Kunihiko
Yamamura, Kenzo
Kato, Aki
Ohashi, Katsuyo
BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (21) : 7675 - 7699

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