-
Dong Xiao,
Anandan Palani,
Xianhai Huang,
Michael Sofolarides,
Wei Zhou,
Xiao Chen,
Robert Aslanian,
Zhuyan Guo,
James Fossetta,
Fang Tian,
Prashant Trivedi,
Peter Spacciapoli,
Charles E Whitehurst,
Daniel Lundell
[show abstract]
[hide abstract]
ABSTRACT: Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.
Bioorganic & medicinal chemistry letters 04/2013; · 2.65 Impact Factor
-
Dong Xiao,
Anandan Palani,
Michael Sofolarides,
Robert Aslanian,
Robert E West,
Shirley M Williams,
Ren-Long Wu,
Joyce Hwa,
Christopher Sondey,
Jean Lachowicz,
Walter A Korfmacher
[show abstract]
[hide abstract]
ABSTRACT: A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
Bioorganic & medicinal chemistry letters 03/2012; 22(9):3354-7. · 2.65 Impact Factor
-
Xianhai Huang,
Jing Su,
Ashwin U Rao,
Haiqun Tang,
Wei Zhou,
Xiaohong Zhu,
Xiao Chen,
Zhidan Liu,
Ying Huang,
Sylvia Degrado, Dong Xiao,
Jun Qin,
Robert Aslanian,
Brian A McKittrick,
Scott Greenfeder,
Margaret van Heek,
Madhu Chintala,
Anandan Palani
[show abstract]
[hide abstract]
ABSTRACT: Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.
Bioorganic & medicinal chemistry letters 12/2011; 22(2):854-8. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.
Bioorganic & medicinal chemistry letters 12/2011; 22(2):1068-72. · 2.65 Impact Factor
-
Xianhai Huang,
Xiaohong Zhu,
Xiao Chen,
Wei Zhou, Dong Xiao,
Sylvia Degrado,
Robert Aslanian,
James Fossetta,
Daniel Lundell,
Fang Tian,
Prashant Trivedi,
Anandan Palani
[show abstract]
[hide abstract]
ABSTRACT: A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.
Bioorganic & medicinal chemistry letters 11/2011; 22(1):65-70. · 2.65 Impact Factor
-
Dong Xiao,
Anandan Palani,
Michael Sofolarides,
Ying Huang,
Robert Aslanian,
Henry Vaccaro,
Liwu Hong,
Brian McKittrick,
Robert E West,
Shirley M Williams,
Ren-Long Wu,
Joyce Hwa,
Christopher Sondey,
Jean Lachowicz
[show abstract]
[hide abstract]
ABSTRACT: A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.
Bioorganic & medicinal chemistry letters 01/2011; 21(2):861-4. · 2.65 Impact Factor
-
Jun Qin,
Ashwin Rao,
Xiao Chen,
Xiaohong Zhu,
Zhidan Liu,
Xianhai Huang,
Sylvia Degrado,
Ying Huang, Dong Xiao,
Robert Aslanian, [......],
Constance Farley,
John Cook,
Stan Kurowski,
Qiu Li,
Margaret van Heek,
Madhu Chintala,
Ganfeng Wang,
Yunsheng Hsieh,
Fangbiao Li,
Anandan Palani
[show abstract]
[hide abstract]
ABSTRACT: Nicotinic acid has been used clinically for decades to control serum lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and lipoprotein-a (LPa), and it is also effective in raising high-density lipoprotein (HDL)-cholesterol. However, nicotinic acid has several side effects in clinical use. The most notable is intense cutaneous vasodilation “flushing” on the upper body and face. We discovered a pyranopyrimidinedione series to be nicotinic acid receptor agonists. A potent nicotinic acid receptor agonist from this series {5-(3-cyclopropylpropyl)-2-(difluoromethyl)-3H-pyrano[2,3-d]pyrimidine-4,7-dione}with reduced flushing side effect in dogs was identified.Keywords (keywords): Nicotinic acid; agonist; flushing; dyslipidemia; VLDL; HDL
12/2010;
-
Dong Xiao,
Cheng Wang,
Anandan Palani,
Hon-Chung Tsui,
Gregory Reichard,
Sunil Paliwal,
Neng-Yang Shih,
Robert Aslanian,
Ruth Duffy,
Jean Lachowicz,
Geoffrey Varty,
Cynthia Morgan,
Fei Liu,
Amin Nomeir
[show abstract]
[hide abstract]
ABSTRACT: Modification of prototype NK(1) antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK(1) antagonists.
Bioorganic & medicinal chemistry letters 11/2010; 20(21):6313-5. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.
Bioorganic & medicinal chemistry letters 01/2009; 19(3):783-7. · 2.65 Impact Factor
-
Sunil Paliwal,
Gregory A Reichard,
Sapna Shah,
Michelle Laci Wrobleski,
Cheng Wang,
Carmine Stengone,
Hon-Chung Tsui, Dong Xiao,
Ruth A Duffy,
Jean E Lachowicz,
Amin A Nomeir,
Geoffrey B Varty,
Neng-Yang Shih
[show abstract]
[hide abstract]
ABSTRACT: Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious gamma-lactam series of selective NK(1) antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.
Bioorganic & medicinal chemistry letters 08/2008; 18(14):4168-71. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A new efficient two-step synthesis of 2,4-dihydro-3H-1,2,4-triazolin-3-ones (triazolinones) from readily available amines is reported. Our novel conditions using hexamethyl disilazane, bromotrimethylsilane, and a catalytic amount of ammonium sulfate smoothly cyclize 1-formyl and 1-acetyl semicarbazides to the target triazolinones. This transformation features simultaneous manipulation of N- and O-nucleophilicity as well as differentiation of the nucleophilicity of a urea and an acyl carbonyl.
Organic Letters 01/2005; 6(25):4795-8. · 5.86 Impact Factor
-
Tetrahedron Asymmetry 17(18):2596-2598. · 2.65 Impact Factor
-
Sunil Paliwal,
Gregory A. Reichard,
Sapna Shah,
Michelle Laci Wrobleski,
Cheng Wang,
Carmine Stengone,
Hon-Chung Tsui, Dong Xiao,
Ruth A. Duffy,
Jean E. Lachowicz,
Amin A. Nomeir,
Geoffrey B. Varty,
Neng-Yang Shih
Bioorganic & Medicinal Chemistry Letters. 18(14):4168-4171.
