Synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 and enantio-dependency of its positive allosteric modulation of prostacyclin receptor

Kohki Yamamoto; Toshifumi Suzuki; Riyo Imamura; Tetsuo Nagano; Takayoshi Okabe; Hiroyuki Miyachi

doi:10.1016/j.bmcl.2017.03.083

Synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 and enantio-dependency of its positive allosteric modulation of prostacyclin receptor

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2567-2570. doi: 10.1016/j.bmcl.2017.03.083. Epub 2017 Mar 29.

Authors

Kohki Yamamoto¹, Toshifumi Suzuki², Riyo Imamura³, Tetsuo Nagano³, Takayoshi Okabe³, Hiroyuki Miyachi⁴

Affiliations

¹ Graduate School of Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
² Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁴ Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: miyachi_hiroyuki@mol.f.u-tokyo.ac.jp.

PMID: 28462839
DOI: 10.1016/j.bmcl.2017.03.083

Abstract

We present a practical synthesis of both enantiomers of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1 (1), which is a positive allosteric modulator (PAM) of prostacyclin receptor (IP) and a candidate for treatment of pulmonary arterial hypertension without the side effects caused by IP agonists. Assay of cAMP production by CHO-K1 cells stably expressing human IP clearly demonstrated that the IPPAM activity resides exclusively on the R-form of 1.

Keywords: Positive allosteric modulator; Prostacyclin; Prostacyclin receptor; Pulmonary arterial hypertension; Tetrazole derivative.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Animals
Antihypertensive Agents / chemical synthesis
Antihypertensive Agents / chemistry*
Antihypertensive Agents / therapeutic use
CHO Cells
Cricetinae
Cricetulus
Cyclic AMP / metabolism
Humans
Hypertension, Pulmonary / drug therapy
Receptors, Epoprostenol / agonists
Receptors, Epoprostenol / genetics
Receptors, Epoprostenol / metabolism*
Stereoisomerism
Tetrahydroisoquinolines / chemical synthesis
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / therapeutic use

Substances

Antihypertensive Agents
Receptors, Epoprostenol
Tetrahydroisoquinolines
Cyclic AMP